NIAMS Long-Range Plan: Fiscal Years 2015-2019

June 18, 2014

TABLE OF CONTENTS

EXECUTIVE SUMMARY

INTRODUCTION

CROSS-CUTTING TOPICS

  1. HEALTH DISPARITIES
    1. Biological Mechanisms
    2. Health Outcomes
    3. Scientific Workforce
  2. TRAINING AND CAREER DEVELOPMENT
  3. INFORMATION DISSEMINATION AND OUTREACH
    1. Information Dissemination
    2. Outreach
DISEASE AND TISSUE-SPECIFIC TOPICS
  1. ARTHRITIS AND RHEUMATIC DISEASES
    1. Genetics and Genomics
      1. Genes and pathways, epigenetics, and gene-environment interactions
      2. Translation of genetic and genomic research from bench to bedside
    2. Mechanisms of Disease
      1. Immune and inflammatory mechanisms
      2. Target organ damage
      3. Pain
    3. Preclinical and Translational Research
      1. Model systems
      2. Therapy development
      3. Biomarkers
      4. Imaging
    4. Clinical Research
      1. Epidemiology and health services research
      2. Clinical trials
    5. Behavioral and Biopsychosocial Research
      1. Behavioral
      2. Psychosocial
      3. Therapies
  2. SKIN BIOLOGY AND DISEASES
    1. Trans-discipline Basic Studies
      1. Skin molecular and cell biology
      2. Stem cells
      3. Developmental biology
    2. Skin as a Barrier
      1. Keratinocytes (epidermis)
      2. Skin photobiology and melanocytes
      3. Fibroblasts and extracellular matrix
      4. Vasculature
      5. Breach of the barrier
    3. Skin as an Immune Organ
      1. Immunobiology of the skin
      2. Inflammatory and immune skin diseases
    4. Skin as a Sensory and Endocrine Organ
    5. Skin Appendages
    6. Genetics of Skin Diseases and Birth Defects
    7. Regenerative Medicine
      1. Skin embryonic development
      2. Tissue neogenesis
      3. Engineered skin tissues
    8. Technology and Instruments
    9. Model Systems
      1. Animal models
      2. In vitro cell-based models
      3. In silico modeling
    10. Therapy Development
      1. Gene and cell-based therapy
      2. Cutaneous and transcutaneous drug delivery
      3. Physical therapies
    11. Clinical Research
      1. Clinical trials and outcomes measures
      2. Epidemiology and health services research
      3. Prevention studies
    12. Behavioral and Biopsychosocial Research
  3. BONE BIOLOGY AND DISEASES
    1. Biology and Physiology of Bone
      1. Molecular and cellular mechanisms in bone
      2. Integrated physiology and pathophysiology of bone
      3. Genetics and genomics of bone mass and fracture risk
    2. Developmental Biology and Stem Cells
      1. Skeletal development
      2. Stem cells
    3. Imaging and Biomarkers of Bone Quality and Fracture Risk
      1. Non-invasive measures of bone quality and fracture risk
      2. Outcome measures and surrogate markers
    4. Preclinical and Translational Research
      1. Pathobiological mechanisms
      2. Therapeutic mechanisms
      3. Gene-based therapies
    5. Clinical Research
      1. Personalized medicine and clinical trials
      2. Disease prevention and health promotion
  4. MUSCULOSKELETAL BIOLOGY AND DISEASES
    1. Biology, Structure, and Function
      1. Molecular and cellular biology of musculoskeletal tissues
      2. Pathogenesis of osteoarthritis
    2. Regenerative Medicine
      1. Multidisciplinary research teams
      2. Biological therapy development
      3. Scaffolds and biomaterials for tissue engineering
      4. Enabling technologies
      5. Functional integration
    3. Preclinical and Translational Research into Joint Replacements
      1. Implant deterioration and failure
      2. Improved materials
      3. Tools for testing
    4. Biochemical and Imaging Biomarkers
      1. Identification, qualification, and validation
      2. Resource development and application
    5. Clinical Research
      1. Behavioral and psychosocial research
      2. Childhood musculoskeletal conditions
      3. Osteoarthritis
      4. Joint replacement
      5. Spinal disorders
      6. Fractures and other types of musculoskeletal trauma
      7. Sports and fitness
  5. MUSCLE BIOLOGY AND DISEASES
    1. Skeletal Muscle Biology
      1. Cell and Developmental Biology
      2. Cell Physiology and Biophysics
      3. Integrated Physiology and Metabolism
      4. Pathophysiology
    2. Preclinical Translation and Therapy Development
      1. Development and use of model systems
      2. Preclinical therapy development
    3. Clinical Translation
      1. Observational cohort studies of muscle diseases
      2. Clinical trials for muscle diseases

CONCLUSION

APPENDICES


EXECUTIVE SUMMARY

PLACEHOLDER TEXT

INTRODUCTION

The NIAMS supports a broad range of research, training, and information dissemination activities. Some conditions within the NIAMS mission are very common while some are rare, affecting only a few thousand people world-wide. The 2010 Global Burden of Disease data has yielded numerous publications regarding the extent to which many conditions within the NIAMS mission affect society. For example, the 30 leading causes of disability in the United States, as measured in years lived with disability (YLDs), include low back pain, other musculoskeletal disorders, osteoarthritis, rheumatoid arthritis and eczema (which rank as numbers 1, 3, 9, 23 and 25, respectively).1 The high ranking of “other musculoskeletal disorders” provides some insight into the magnitude of the burden that numerous diseases covered by the NIAMS mission places on society. The Global Burden of Disease 2010 study defines the category “other musculoskeletal disorders” as including relatively common disorders such as ankylosing spondylitis, fibromyalgia, psoriatic arthritis, scleroderma, and systemic lupus erythematosus, as well as rare diseases such as the autoinflammatory condition Bechet’s disease, various forms of juvenile arthritis, the inflammatory muscle disease polymyositis, rare systemic connective tissue disorders such as Ehlers-Danlos syndrome and Marfan syndromes, and different types of vasculitis (e.g., polyarteritis and Wegener's granulomatosis).2 Given the burden that arthritis and musculoskeletal and skin conditions of all types also place on the global population3 , it is not surprising that they affect people of all ages and of all racial and ethnic backgrounds. Combined, they afflict tens of millions of Americans, cause tremendous human suffering, and cost the United States economy billions of dollars in health care and lost productivity.

The mission of the NIAMS is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. It is critical to revisit our program areas periodically because research needs, opportunities, and challenges change. The NIAMS Long-Range Plan for FY 2015-2019 will facilitate communication between the Institute and its many constituents – scientific communities, health care providers, health advocacy organizations, the general public, and the Congress – about needs and opportunities related to the NIAMS mission.

The purpose of the NIAMS Long-Range Plan for FY 2015-2019 is to continue to promote exploration of ideas and encourage new research directions as needed. Although the NIAMS will continue to devote the majority of its extramural budget toward funding the best investigator-initiated research ideas, we must also continue to rise to the challenge of serving the scientific community in the best possible way. The plan brings attention to many areas that could be explored in the coming years to propel research progress related to the understanding, diagnosis, treatment and ultimately, prevention, of diseases within the NIAMS mission.

The plan is not comprehensive; it does not mention every research area or disease of interest by name. As a broad scientific outline for NIAMS, however, it informs the Institute’s priority setting process while enabling the Institute to adapt to the rapidly changing biomedical and behavioral science landscapes.

Through responsible stewardship of taxpayer dollars, the NIAMS promotes exploration of a broad spectrum of highly meritorious research. To facilitate this process, the NIAMS will continue to partner with a variety of public and private organizations to advance research within our mission areas. Through these efforts, the NIAMS will be able to leverage existing resources and explore many scientific areas in ways that the Institute would not be able to do alone. By supporting research that is complementary to programs supported by other NIH Institutes and Centers, the NIAMS will be able to broaden the impact of scientific advances and continue toward our goal of improving the quality of life of all Americans affected by diseases of the bones, joints, muscles, and skin.

1 US Burden of Disease Collaborators. JAMA. 2013. PMID: 23842577
2 Smith E, et al. Ann Rheum Dis. 2014. PMID: 24590181
3Murray CJ, et al. Lancet. 2012. PMID: 23245608

CROSS-CUTTING TOPICS

The NIAMS Long-Range Plan for FY 2015-2019 is organized into five disease- and tissue-specific topics—Arthritis and Rheumatic Diseases, Skin Biology and Diseases, Bone Biology and Diseases, Musculoskeletal Biology and Diseases, and Muscle Biology and Diseases—each of which is divided into categories and broad areas of potential research directions, needs and opportunities. The NIAMS recognizes that overlapping areas exist within each topic, and fully expects many advances to arise as a consequence of research performed in additional fields, as well.

We have also described three cross-cutting areas, highlighting needs and opportunities that are relevant to many of our research communities. These categories include Health Disparities, Training and Career Development, and Information Dissemination and Outreach.

  1. Health Disparities

    Most of the diseases in the NIAMS mission areas are chronic, and many cause life-long pain, disability, or disfigurement. They affect millions of Americans; cause tremendous human suffering; and cost the U.S. economy billions of dollars in health care and lost productivity. These conditions affect people of all ages, racial and ethnic populations, and economic groups. Many affect women and minorities disproportionately—both in increased numbers and increased disease severity. For example, women with systemic lupus erythematosus (SLE) patients outnumber men, nine to one. African American women are three times as likely to get SLE as Caucasian women, and the disease is also more common in Hispanic, Asian, and American Indian women. SLE risk genes have been identified on the X chromosome, which provides potential evidence for the sex bias in this autoimmune disease. Rheumatoid arthritis, osteoporosis, and osteoarthritis (in patients over 45 years of age) are also more prevalent among women, whereas certain forms of ankylosing spondylitis (inflammation of the joints in the spine) occur more frequently in men.

    Factors such as socioeconomic status, education level, cultural issues, and medical practices may contribute to health disparities after disease onset, potentially affecting disease progression and treatment response. Understanding the role that these issues play can help inform the development of strategies that reduce outcome disparities, and will allow for early diagnosis and disease management tailored to the individual patient’s needs.

    The NIH Revitalization Act of 1993 (Public Law 103-43) requires the inclusion of women and minorities in NIH-funded clinical research, unless there is appropriate justification for not including them. Researchers need to consider factors such as sex, race, ethnicity, and socioeconomic status in the design, data collection, and analysis of clinical research studies and clinical trials. These studies could, therefore, serve as resources for data that could be leveraged to answer important, fundamental questions in health disparities research, including:

    • Establish the current degree of disparities, to allow a rigorous evaluation of progress toward their reduction or elimination.
    • Develop standards of clinical data features for health disparities.
    • Identify areas ready for immediate study, such as those where health disparities due to minority or socioeconomic status are well documented.
    • Use administrative databases (e.g., billing, pharmacy) as a source of data associated with population groups to examine research topics such as medical compliance (e.g., adherence to taking bisphosphonates after hip surgery).

    The following are some of the key research needs and opportunities in this area:

    1. Biological Mechanisms

      • Investigate genetic, biological, and environmental mechanisms underlying increased susceptibility to and severity of disease among different racial and ethnic populations.
      • Expand research on autoimmune diseases with female preponderance, and elucidate associated pathogenic pathways.
      • Explore how sex disparities in diagnosis or treatment may be related to symptom descriptions by patients, unconscious bias of physicians, or treatment response, and how physicians and researchers could be trained to compensate for these differences.
      • Understand how comorbid conditions associated with particular groups (e.g., diabetes, kidney disease) may contribute to disparities in disease severity.
    2. Health Outcomes

      Conduct behavioral research investigating cultural issues that can influence disease management and outcomes (e.g., risk behaviors and medical compliance), and incorporate findings into patient education strategies to promote adoption of healthy behaviors.

      • Investigate factors that affect outcomes for rural, underserved, and minority populations, including health insurance, reimbursement, and socioeconomic factors. Examine ways that treatment protocols could be modified to better serve those populations.
      • Expand the use of electronic medical record (EMR) data to facilitate the exploration of outcomes disparities for individuals with differing socioeconomic status who receive standard care, and reveal if factors such as access to subspecialty care, missed follow-up appointments, etc., are contributing.
      • Pursue research on diseases with significant effects on the health and quality of life of minority populations (e.g., vitamin D insufficiency, vitiligo, and keloids).
    3. Scientific Workforce

      • Develop a diverse, culturally competent workforce in biomedical research and health care, to expand interest and commitment to reducing health disparities.
      • Encourage the development of a “critical mass” of researchers actively pursuing health disparities research, either through expansion of the scope of projects to include health disparities elements, or by engaging health disparities researchers from other disciplines to initiate projects within NIAMS’ mission areas.
  2. TRAINING AND CAREER DEVELOPMENT

    The NIAMS is committed to ensuring that a diverse and highly skilled workforce is available to assume leadership roles in biomedical and behavioral research. The Institute encourages and supports trainees at all levels through the use of predoctoral and postdoctoral training programs and fellowships, mentored career development awards, and grants for newly independent investigators. The NIAMS also partners with professional societies and other organizations to ensure that a comprehensive and complementary portfolio of training opportunities is available.

    The NIAMS participates in trans-NIH programs to encourage young investigators to begin exploring projects in arthritis, musculoskeletal, and skin diseases research. Predoctoral fellows in Ph.D. or formal dual degree programs (M.D/Ph.D., etc.) and postdoctoral fellows may be eligible for individual Ruth L. Kirschstein National Research Service Awards (NRSAs). Universities and other eligible organizations can apply for institutional NRSAs that provide support for both predoctoral and postdoctoral trainees.

    In addition to encouraging trainees to enter NIAMS’ mission areas, the NIAMS employs several mechanisms to provide clinicians with protected time to develop their research skills. The NIH Mentored Clinical Scientist Research Development Award (K08) supports clinicians for an intensive research experience in basic and translational research. The NIH Mentored Patient-Oriented Research Career Development Award (K23) is targeted to clinically trained professionals who intend to focus their research careers on patient-oriented research. The NIH Midcareer Investigator Award in Patient-Oriented Research (K24) provides protected time for mid-career clinicians to conduct patient-oriented research and to act as mentors for junior clinical investigators. Clinicians are also encouraged to apply to the NIH Loan Repayment Program (LRP), which helps pay for qualified student loan debt. The NIAMS will continue to utilize these mechanisms to help ensure a robust pipeline of clinical researchers.

    The NIAMS also participates in programs focused on support for new and early stage investigators, a high priority for the NIH. For example, the Pathway to Independence Award (K99/R00) program is designed to facilitate a timely transition from a mentored postdoctoral research position to a stable independent research position at an earlier stage than the current norm. In addition, new investigators are given special consideration during review and during funding decisions at NIAMS. Information on these programs, as well as others focused on training and career development, can be found at http://niams.nih.gov/Funding/Funding_Opportunities/activity_codes.asp. Through an ongoing assessment of needs and opportunities, the NIAMS has maintained a multi-dimensional approach to training and career development. The Institute's commitment to develop and nurture a healthy pipeline of biomedical researchers focused on the diseases and disorders within NIAMS mission areas will advance science and in the 21st century.

  3. INFORMATION DISSEMINATION AND OUTREACH

    Disseminating information about research progress and conducting outreach to multiple audiences continue to be essential components of the NIAMS mission. The NIAMS is committed to communicating research advances to all segments of the public. The driving force behind NIAMS-funded research is the potential to improve the lives of those who are affected by diseases and conditions of the bones, joints, muscles, or skin.

    1. Information Dissemination

      The Institute is dedicated to working closely with grantee institutions to disseminate research findings to varied audiences via multiple venues. NIAMS long-range plans include:

      • Enhancing access to trustworthy and audience-appropriate health information in multiple languages and formats, with an increasing emphasis on electronic offerings (see box below); and
      • Raising awareness of NIAMS-supported research through plain language descriptions that are widely shared via multiple channels, including social media.
      Information Dissemination and Outreach Resources

      What sort of publications does the NIAMS offer?

      The NIAMS develops health information materials for patients and their families, health care providers, and the general public. The NIAMS offers many of its publications in easy-to-read formats, as well as in Spanish, Chinese, Korean and Vietnamese. In addition, the NIAMS makes available several publications in audio formats for individuals with visual impairments and/or limited literacy skills. A separate Spanish web portal and Asian language landing page enable users to easily access publications in different languages. (http://catalog.niams.nih.gov/subject.cfm?SearchType=AllPubs).

      How do I order publications from the NIAMS?

      Please visit the NIAMS website (http://catalog.niams.nih.gov/) or call 877-226-4267 (TTY 301-565-2966) (toll free call) or e-mail NIAMSinfo@mail.nih.gov. Publications are free.

      How can I stay informed about NIAMS activities?

      Each month, the Institute produces the NIAMS Update, an electronic digest published for those interested in the latest scientific news and resources on diseases of the bones, joints, muscles, and skin. Please visit http://www.niams.nih.gov/News_and_Events/NIAMS_Update/ to subscribe to the NIAMS Update. The Institute also disseminates the NIAMS Multicultural Outreach News, an online digest for those interested in information and resources for multicultural communities. In addition, updates can be received via Twitter (@NIH_NIAMS External Web Site Policy ) and Facebook (NIH.NIAMS External Web Site Policy).

      Where can I find answers to other questions about the NIAMS, its research, or its publications?

      Please visit http://www.niams.nih.gov/About_Us/Contact_Us/faq.asp.

       

      The Institute will continue to support and operate the NIAMS Information Clearinghouse and the NIH Osteoporosis and Related Bone Diseases ~ National Resource Center. Both clearinghouses distribute health education materials to patients, allied health professionals, researchers and scientists, voluntary and professional organizations, underserved and at-risk populations, the media, and the general public. The NIAMS Information Clearinghouse provides materials on diseases and conditions of the bones, joints, muscles, and skin in a variety of formats and languages.

      The National Resource Center provides an important link to resources and information on metabolic bone diseases including osteoporosis, Paget’s disease of bone, and osteogenesis imperfecta. The National Resource Center is supported by the NIAMS with contributions from the National Institute on Aging, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the NIH Office of Research on Women’s Health, and the HHS Office on Women’s Health.

      Social media channels increasingly have become the primary avenues through which people receive their news and interact with organizations. Use of social media provides a direct link to people affected by diseases in the NIAMS research portfolio and to researchers around the world. To that end, the NIAMS has fully integrated social media into its information dissemination program. The Institute posts regular updates to Twitter (@NIH_NIAMSExternal Web Site Policy) and Facebook (NIH.NIAMSExternal Web Site Policy), featuring NIAMS health publications, news and announcements, and other informational resources. The NIAMS will continue its efforts to reach more people via social media channels, and explore the use of other social media tools, such as Twitter chats, to increase direct interaction with its audiences.

      Looking ahead to other electronic communication efforts, the NIAMS is exploring the conversion of print publications to digital formats and the use of electronic publications. The Institute is also exploring a NIAMS website redesign, including the enhancement of a mobile friendly and responsive website.

    2. Outreach

      The Institute is dedicated to engaging the public and encouraging broad participation and input in NIAMS and NIH activities. Long-range plans in this area include:

      • Increasing visibility of the NIAMS as a leading resource for research-based information on diseases and conditions of the bones, joints, muscles, and skin; and
      • Expanding understanding among scientists and students about careers and training opportunities in biomedical research fields in NIAMS mission areas, particularly in underrepresented communities.

      The Institute works closely with the NIAMS Coalition to share the latest research advances and related developments, and to foster dialogue on the future path and directions of NIAMS-funded research. The NIAMS Coalition is an independent entity consisting of a large group of professional and voluntary organizations that work to raise awareness about research into the basic understanding, causes, incidence, treatment and prevention of diseases of the bones, joints, muscles, and skin. It plays a vital role as a liaison among researchers supported by the Institute, the patients who benefit from the Institute’s research investments, Congress, and the American public. The Institute will continue to engage regularly with Coalition members through teleconferences and webinars, in-person meetings, opportunities to meet with Institute leadership, and presentations at professional and voluntary meetings.

      The NIAMS will continue its National Multicultural Outreach Initiative, a project to ensure that research results and health information reach diverse populations. Through the development and distribution of four culturally tailored health planners and other materials, people in multicultural communities nationwide receive access to health information and resources for managing conditions of the bones, joints, muscles and skin. An electronic toolkit is available on the website to assist voluntary and professional organizations in multicultural outreach. Further, the NIAMS is implementing a Language Access Plan, as part of NIH-wide efforts to help ensure that individuals who have limited English proficiency have meaningful access to all NIAMS programs and activities.

      To broaden our outreach to underrepresented groups, the NIAMS has taken an active role in leading the Trans-NIH American Indian/Alaska Native (AI/AN) Health Communications and Information Work Group – a collaboration that represents 20 NIH Institutes, Centers and Offices – to coordinate NIH efforts to develop and disseminate health information targeting AI/AN communities. The Work Group has partnered with the Indian Health Service's National Community Health Representative Program on an outreach activity to raise awareness of NIH health resources among its network of 1600 Tribal employees who serve as lay health educators and patient liaisons in Native communities nationwide. It is pursuing a similar outreach effort with the Administration on Aging / Administration for Community Living’s Title VI grantees to provide services to Native elders and caregivers.

DISEASE AND TISSUE-SPECIFIC TOPICS

  1. ARTHRITIS AND RHEUMATIC DISEASES

    The NIAMS Arthritis and Rheumatic Diseases programs address basic, translational, and clinical research in immune-mediated arthritis and autoimmune-related acute and chronic disorders. These include, but are not limited to, the adult diseases of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE, or lupus), crystalline-induced diseases (gout, calcium pyrophosphate dihydrate crystal deposition disease, hydroxyapatite crystal disease), the spondyloarthropathies (ankylosing spondylitis, psoriatic arthritis), reactive, enteropathic and infectious arthritis, scleroderma, vasculitides (giant cell arteritis, polymyalgia rheumatica, granulomatosis with polyangiitis) and Sjögren's syndrome. Others include pediatric diseases, such as juvenile idiopathic arthritis, periodic fever syndromes, and juvenile lupus, which generally has a more severe onset and disease course than the adult form of lupus. In particular, the NIAMS Arthritis and Rheumatic Diseases programs support studies focused on the basic biology of autoimmunity and inflammation, to better understand the molecular mechanisms underlying these processes, with the goal of finding ways to interrupt them and improve patient-centered outcomes. The Institute is pursuing opportunities in genetics and genomics research, clinical trial design and conduct, chronic pain, and biopsychosocial aspects of diseases in this portfolio, as well as identification of risk factors for these disorders. Osteoarthritis is covered in Bone Biology and Diseases and Musculoskeletal Biology and Diseases.

    1. Arthritis and Rheumatic Diseases: Genetics and Genomics

      Rheumatologists have long recognized the incidence of many rheumatic diseases within families and certain ethnic populations, pointing to some role of genetic risk. Scientists' perseverance in gathering biospecimens and clinical histories from patients and their relatives, along with the explosion of knowledge and techniques in genetics and genomics, have opened new avenues of research. Emerging opportunities to study genes and pathways, epigenetics, and gene-environment interactions are expected to provide novel insights into disease mechanisms, and ultimately lead to development of better tools for diagnosis, prognosis, prevention, and treatment.

      1. Genes and pathways, epigenetics, and gene-environment interactions

        Genome-wide association studies (GWAS) have led to significant advances in understanding complex rheumatic disorders by facilitating the identification of common genetic variants of modest effect that influence disease risk. Despite promising results, the functions of the identified variants are largely unknown; and follow-up studies are needed to understand the mechanisms by which they may contribute to biology and disease. A growing body of data generated through efforts such as the Encyclopedia of DNA Elements (ENCODE) Project and the NIH Epigenomics Program has enabled researchers to extend the results of GWAS studies through genome-wide analysis of transcription, chromatin organization, and epigenetic marks. Findings indicate that the majority of variants identified by GWAS fall in the non-protein-coding regions of the genome.

        Recent data suggest that environmental factors may directly influence disease risk by interacting with the genome to alter gene expression. Analyses of gene-environment interactions are expected to provide information about the relationships between rheumatic diseases and alterations in DNA methylation and chromatin remodeling, RNA transcripts and their encoded proteins, and microRNAs. Research on genes or variants that interact with environmental factors (e.g., gut microbes, dietary components, infectious agents) to trigger disease may provide important insights into the development, progression, and severity of rheumatic diseases.

        Broad areas of potential research directions include:

        • Understand the biology of genetic variants identified through GWAS, including the role of gene regulation, non-coding RNA [e.g., microRNA and long non-coding RNAs (lncRNAs)], and epigenetic regulation, in relevant cell types.
        • Leverage publically available data resources such as the ENCODE Project and NIH Epigenomics Program, as well as novel computational and bioinformatics tools, to guide or prioritize functional analyses of causal variants.
        • Expand on next generation sequencing (e.g., through whole genome sequencing) and other novel technologies to identify a full spectrum of variants associated with disease susceptibility.
        • Apply novel strategies to dissect the major histocompatibility complex (MHC) loci associated with rheumatic diseases.
        • Apply novel gene editing techniques, such as CRISPR/Cas or TALENs, to assess the function of candidate variants in relevant model systems (e.g., induced pluripotent stem cells), and knock-in or knockout (e.g., RNAi) in vitro and in vivo models.
        • Study gene-gene, gene-protein, and gene-environment interactions. Explore single-cell genomics such as RNA-sequencing in relevant tissues and cell types.
        • Explore crowdsourcing or other novel approaches to expand patient sample sizes and acquisition of longitudinal data, and enhance broad sharing of data to facilitate genetic and genomics studies.
      2. Translation of genetic and genomic research from bench to bedside

        The rapidly progressing fields of genetics and genomics offer powerful tools for drug discovery and for studies of the influence of genomic variations on drug response by correlating gene expression or SNPs with drug efficacy or toxicity. The application of genomic approaches to therapies used in arthritis and rheumatic diseases holds great promise for "personalized medicine," in which genetic information can facilitate diagnosis, and treatment can be guided by an individual's unique genetic makeup (see box below).

        Using Genetic Analysis for Drug Discovery in Rheumatoid Arthritis:

        Many biological pathways, including those of the immune system, are perturbed in patients with rheumatoid arthritis (RA). Determining which of them should be the focus of drug development efforts is an enormous challenge because only some of those pathways cause the disease. Using a systematic strategy that integrates genetic findings with diverse genomic and biologic data, an international team of researchers has shown that a number of molecular targets of known drugs are on the list of RA disease genes revealed by comprehensive genetic analyses, suggesting that some of these drugs might be re-purposed for the treatment of RA. Researchers have also uncovered several new candidate drug targets based on the genetic and genomic information. The study highlights the potential of human genetics to shed light on genes and pathways that contribute to the onset of disease, and the application of genetics as a valuable tool to prioritize molecular targets for novel therapeutic testing in RA and other related complex diseases. For further information see Arthritis Genetics Aids Drug Discovery.

         

        Broad areas of potential research directions include:

        • Apply novel, robust genetic and genomic approaches to understand disease mechanisms, as well as differences in treatment responses and drug toxicities.
        • Elucidate the role of epigenetic mechanisms in the onset and progression of rheumatic diseases.
        • Link developments in genetics, genomics, proteomics, bioinformatics, and systems biology to clinically relevant issues, particularly the prediction, prevention, and monitoring of rheumatic diseases.
        • Use genetic and genomic findings to inform drug discovery and diagnosis of disease in clinical care.
        • Define disease heterogeneity at the molecular level by applying functional genetic and genomic information, as well as other relevant factors, to the refinement of phenotypes and subcategories of complex diseases.
        • Develop and validate clinically useful models for the prediction of disease risk, progress, and prognosis.
        • Explore the potential of gene-based therapies including gene silencing (e.g., small interfering RNAs with conjugates) and overexpression approaches to treat or prevent disease.
    2. Arthritis and Rheumatic Diseases: Mechanisms of Disease

      1. Immune and inflammatory mechanisms

        Increased knowledge of autoimmunity and basic functioning of the immune system has advanced our understanding of arthritis and other rheumatic diseases. Two arms of the immune system—the innate and adaptive immune systems—coexist as protective and as potentially injurious mechanisms. These systems have evolved to protect us from environmental insults and detect early damage to our cells. Defective regulation of the immune system might result in autoimmune or autoinflammatory diseases. Improved understanding of the immune system, the complex interplay between innate and adaptive immunity, and the interactions between the immune system and various tissues in normal and pathological conditions will lay the groundwork for future therapies for autoimmune diseases.

        1. Innate immunity

          The innate immune system is the body's first line of defense and reacts quickly and broadly to danger by identifying damaged cells as well as invading pathogens, such as bacteria and viruses. It consists of anatomical barriers, networks of soluble mediators, and effector cells.

          The innate immune system uses a limited number of receptors, called pattern recognition receptors (PRRs), to recognize microbial products called pathogen-associated molecular patterns, or PAMPs, as well as mislocalized or damaged molecules from the body called damage-associated molecular patterns, or DAMPs, that arise during states of cell stress.

          The first identified, and best characterized, PRRs are the toll-like receptors (TLRs), which are membrane-bound and expressed on the cell surface and in endosomal compartments. Other types of PRRs include C-type lectin receptors (CLRs), found in both membrane-bound and secreted forms; and a more recently discovered class of PRRs that detects microbial and danger signals inside of cells, such as the NOD-like receptors (NLRs), the retinoic acid-inducible gene I-like receptors (RLRs), and cytosolic DNA sensors such as members of the AIM2 family. Following PRR activation, various signaling cascades initiate or shape an inflammatory response. For example, after recognition of a PAMP or DAMP, a number of NLRs are known to form the framework for multi-protein cytosolic platforms called "inflammasomes," which orchestrate early inflammatory processes. The resulting inflammatory cascade recruits immune cells to the site of infection or damage, triggering expression of molecules needed for the induction of adaptive immunity.

          An example of how the innate immune system may contribute to disease is described in the box below.

          Novel Mechanism for the Development of Inflammation and Tissue Damage in Lupus:

          Research suggests that abnormalities or dysregulation of basic cellular functions and interactions of a variety of immune cell types may be involved as key steps in the development of lupus. Neutrophils, an abundant, yet short-lived type of white blood cell involved in the innate immune response, are thought to contribute to the damage observed in lupus. Recent studies have indicated that neutrophil death by a mechanism called “NETosis” was the likely source of material that elicited an autoimmune response. NETosis occurs when dying neutrophils release a web of DNA coated with anti-microbial proteins, forming a structure called a neutrophil extracellular trap (NET). Current thinking is that lupus is characterized by an imbalance between NET formation and NET clearance, leading to the creation of stable immunogenic material that can activate other immune cells and, ultimately, cause tissue damage. A recent study, using a combination of both human and animal research, describes a novel mechanism, enhanced in patients with lupus, through which NETs activate inflammation in tissues, thus describing a link between NETs and tissue damage in lupus patients. Although molecular mechanisms through which NETs may be promoting inflammation and tissue damage in lupus are just beginning to be identified, such findings may eventually provide novel targets for treatment development leading to improved patient care and outcomes.

          Reference:
          Kahlenberg JM, et al., J Immunol. 2013. PMID: 23267025

           

          Broad areas of potential research directions include:

          • Elucidate the role of the human mucosal and skin microbiome in the etiology of rheumatic diseases.
          • Study the role of innate immune system components—such as DAMPs, PAMPs, PRRs, inflammasomes, and associated signaling pathways—on the initiation and propagation of autoimmune and autoinflammatory diseases.
          • Expand understanding of the cross-regulation between components of the innate and adaptive immune systems in inflammation and rheumatic diseases (e.g., TLR-induced maturation and activation of plasmacytoid dendritic cells to produce type I interferon; direct regulation and activation of TLR-expressing T and B cells in response to TLR ligands).
          • Study the involvement of a wide range of hematopoietic and other cell types in rheumatic diseases. Examples include—but are not limited to—macrophages, monocytes, neutrophils, platelets, dendritic cells, innate lymphoid cells, mast cells, basophils, eosinophils, fibroblasts, and synoviocytes.
          • Understand the contribution of dysregulated cellular processes (e.g., citrullination, cell death, autophagy, unfolded protein response) in the development and progression of autoimmune disorders.
          • Improve understanding of differences in the molecular and cellular components that mediate specific systemic autoimmune diseases.
        2. Adaptive immunity

          In contrast to the innate immune system, the adaptive immune system provides more specific, targeted, and sustained responses. Successful adaptive immunity against a broad range of pathogens depends on the body's ability to produce randomly generated, diverse receptors on the surface of lymphocytes. Because of the enormous number of antigens that the body routinely encounters, and their potential similarity to self-components, the adaptive immune system is at risk of producing self-reactive (autoreactive) cells that can trigger autoimmunity. Immune tolerance addresses this problem by either removing autoreactive cells from the system or by diminishing their reactivity enough to prevent disease. Autoimmune disease can occur when there is a breach or dysregulation in this process of immune tolerance. Thus, a better understanding of the mechanisms of adaptive immunity and autoimmune diseases may help in the development of antigen-specific and/or autoreactive cell-specific therapies that leave protective, global immune function intact.

          Broad areas of potential research directions include:

          • Clarify the role of the major histocompatibility complex and antigen-presenting cells in autoimmunity.
          • Further define the role of T cell and B cell subsets and functional plasticity in immune responses and autoimmune rheumatic diseases.
          • Expand understanding of autoantigen expression in rheumatic diseases, including the role of metabolic and other changes (e.g., citrullination) in tissue or organ environments that lead to autoantigen production.
          • Develop novel techniques to identify autoantigens involved in rheumatic diseases.
          • Define and characterize mechanisms that control tolerance to self and the production of autoantibodies.
          • Explore mechanisms of remission and exacerbation of autoimmune diseases.
          • Investigate the established roles of B cells in autoimmune diseases (autoantibody production), as well as their more newly elaborated functions (antigen presentation and co-stimulation during initiation of immune responses, and the release of inflammatory and immunomodulatory cytokines).
          • Elucidate the mechanisms by which sex hormones, sex-specific gene products (e.g., X and Y chromosome products), and other sex specific factors (e.g., pregnancy) influence immune functions, in an effort to understand why autoimmunity is so much more common in women.
        3. Inflammation and inflammatory mediators

          Chronic inflammation is a characteristic of many autoimmune diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, inflammatory myopathies, and lupus. Inflammation causes swelling, pain, and damage to organs. Research advances concerning the molecular and cellular contributors to this condition have provided critical insights into the potential causes of inflammation. Understanding both triggers and amplifiers of inflammation will help researchers design targeted therapies.

          Broad areas of potential research directions include:

          • Explore the role of specific cytokines, chemokines, icosanoids and other lipid-based signaling molecules, proteases (including the neutral proteases from mast cells), inhibitors of proteases, as well as receptors for these molecules in the autoimmune and inflammatory components of rheumatic diseases.
          • Conduct further research in the development and biological functions of T cell subsets, as related to the inflammatory process in rheumatic diseases (e.g., the role of regulatory T cells in ameliorating inflammation).
          • Identify and characterize molecular mechanisms that either resolve or dampen inflammation (e.g., anti-inflammatory cytokines, chemokine/chemokine receptors and "decoys," lipid-derived mediators, leukocyte apoptosis).
          • Investigate the influence of immune cell trafficking on disease mechanisms, including the identification of key players in leukocyte migration from the vasculature to surrounding tissues (extravasation), and examination of the roles of the adhesion molecules and chemoattractants that mediate cell trafficking.
          • Study potential environmental triggers of pathogenic pathways and inflammation, such as infection (as in Lyme disease), occupational exposures, smoking, diet, and inflammation-associated factors.
          • Enhance understanding of the genetics and mechanisms of autoinflammatory disorders (e.g., role of cytokines such as IL-1 and TNF-alpha) to improve diagnosis and treatment of these diseases.
      2. Target organ damage

        The manifestations of rheumatic diseases can be diverse and may affect many organs and organ systems, including the skin, joints, and other internal organs, such as the kidneys, heart, lungs, blood vessels, and the brain. Although immune dysregulation plays a major role in these diseases, structure and function of target organs such as the vasculature may contribute significantly to the development of tissue damage and clinical disease. A better understanding of mechanisms of tissue damage may suggest how to modify these processes and approaches to minimize or prevent some of the most serious complications of autoimmune disease.

        Broad areas of potential research directions include:

        • Explore the interrelationships between immune response components (both innate and adaptive) and target tissues or organs (e.g., synovium in rheumatoid arthritis, kidney in lupus) in normal and pathological conditions.
        • Investigate the role of non-immune mechanisms (e.g., hypoxia, fibrosis, and metabolic changes) in tissue injury.
        • Characterize and understand how autoantibodies cause disease.
        • Elucidate the effector mechanisms of tissue damage (e.g., complement, cytokines, and immune complexes).
        • Investigate how organ responses may sustain inflammatory disease.
        • Identify associations between chronic inflammation and the initiation and progression of cardiovascular disease in arthritic and rheumatic diseases.
        • Understand the roles of blood vessels and vascular endothelium in the pathogenesis of inflammatory rheumatic diseases.
        • Investigate the function of neurons that innervate lymphoid tissues, and characterize the links between immune dysfunction and nervous system involvement in rheumatoid arthritis, lupus, scleroderma, and other rheumatic diseases.
      3. Pain

        Chronic pain is an important aspect of many of the diseases within the NIAMS portfolio. The contribution of chronic pain to patient suffering and burden, particularly when worsened by acute conditions, is likely to increase substantially as the U.S. population ages. Many clinically important aspects of pain are not adequately understood. While there have been many developments in the understanding of pain and how it is treated, these have not been easily translated into interventions for chronic pain, which is a serious public health problem. In addition to supporting a broad portfolio of research on chronic pain, the NIAMS also is a member of the NIH Pain Consortium that promotes trans-NIH collaboration on pain research activities.

        Broad areas of potential research directions include:

        • Investigate interactions involving the plasticity of the peripheral and central nervous system, and the plasticity of the inflammatory system, which may contribute collectively to the development and perpetuation of chronic pain.
        • Characterize reversible and permanent biochemical, inflammatory, autoimmune and anatomic changes that cause, or are caused by, chronic pain.
        • Identify a set of biological, behavioral, genetic, epigenetic, cognitive, psychological, and social factors (e.g., the "exposome") that makes an individual susceptible to chronic pain, transition from acute to chronic pain, or from pediatric to adult pain.
        • Study the heterogeneity and epidemiology of pain syndromes to understand their genetic, epigenetic, environmental and social risk factors, the mechanisms by which they develop, and variations in phenotype.
        • Explore and validate both existing and new tools that will allow for accurate diagnosis and optimized, personalized treatment of chronic pain conditions.
        • Explore the use of appropriate animal models of chronic pain to better understand its pathophysiology and etiology and to develop behavioral measures.
        • Develop and validate tools to identify individuals at risk for chronic pain and facilitate early identification of pain to enable early intervention and prevent transition to a chronic state.
        • Develop novel therapeutic approaches to treat chronic pain conditions that encourage the development of analgesic drugs, including non-opioid-based drugs, personalized therapeutics, and behavioral interventions.
    3. Arthritis and Rheumatic Diseases: Preclinical and Translational Research

      Unraveling the complexity of rheumatic diseases requires an understanding of how disease initiation and progression are integrated, so effective and targeted interventions can be developed. Much of this research is conducted in model systems (see below), which leads to further refinement of therapeutic approaches and design before human testing.

      Recent progress in developing molecular and genetic tools (e.g., single-cell analysis, ‘omics technologies, genome editing, sequencing techniques for identifying bacterial isolates) for basic research has facilitated disease-specific investigations (see box below). Preclinical and translational studies are expected to advance knowledge of underlying mechanisms and facilitate the development of therapies that are likely to be adopted into clinical practice.

      Role of the Microbiome in Health and Disease:

      Researchers are investigating the potential connection between health, disease, and the so-called human microbiome—the population of microorganisms that inhabit the human body. Studies suggest that the microbiome plays an important role in maintaining good health, most likely by keeping pathogenic organisms under control. Furthermore, changes in the composition of the microbiome have been associated with a number of diseases. In a recent translational research study, scientists compared the gut microbes of people with new-onset, untreated rheumatoid arthritis to gut microbes present in healthy controls, patients with rheumatoid arthritis who were receiving treatment, and patients with psoriatic arthritis. They found that the bacterium Prevotella copri (P. copri) was more abundant in patients with new-onset, untreated rheumatoid arthritis than in the other groups, suggesting that the bacterium contributes to the development of the disease. The discovery establishes a link between a specific type of gut bacteria and the onset of rheumatoid arthritis, provides a basis for further investigations of the role of the microbiome in rheumatoid arthritis, and holds promise for advancing diagnosis, treatment, and prevention.

      For further information, see Gut Microbes Linked to Rheumatoid Arthritis.

       

      1. Model systems

        Model systems aim to define disease mechanisms, as well as design and test approaches to prevent disease onset and progression. Animal models offer some of the best systems for detailed phenotyping of various diseases and conditions, enabling scientists to identify human disease-related genes and gain a better understanding of how these disease genes work. Current mouse models focus on immune cell function and can recapitulate many aspects of human diseases (e.g., rheumatoid arthritis and lupus), which provides important information about pathogenic and therapeutic pathways and their interactions. Ex vivo or in vitro cell-based systems may also serve as important experimental models for studying arthritis and rheumatic diseases.

        Given the complexity of immune responses, etiologic and mechanistic questions about disease are difficult to answer. By integrating large amounts of research data into a dynamic computer-based model, systems biology approaches can be used to better understand the interrelationships between immune system components over time and their regulation.

        New Model for Scleroderma Research:

        Efforts to improve understanding of the etiology of scleroderma and devise therapies to treat it have been hampered by the lack of proper experimental animal models that mimic the disease. In a recent advance, investigators reported the creation of a mouse model for an inherited form of scleroderma, stiff-skin-syndrome (SSS). Previously, the team mapped the SSS mutation in humans to the gene for the extracellular matrix protein fibrillin-1. In order to create an animal model, they introduced the same mutation into mice and showed that it causes symptoms that are very similar to those seen in humans with SSS. The mutation is suspected to perturb the interaction of fibrillin-1 with cell surface proteins called integrins, which act as sensors of cells’ external environment. The team then tested whether drugs that mimic the interaction between fibrillin-1 and integrins would reverse manifestations of disease, and found that several such agents halted disease progression in the mice. The new model will enable further therapeutic studies for scleroderma. In addition, it provides a powerful example of how a carefully designed animal model can advance our understanding of a complex disease.

        For further information see Novel Insights Into Causes of Scleroderma Offer Potential New Treatment Strategies.

         

        Broad areas of potential research directions include:

        • Develop clinically-relevant animal models for functional and mechanistic studies of pathogenic pathways identified by genome-wide association studies and other human genetics research.
        • Develop animal models that recapitulate molecular abnormalities identified in patients with autoimmune diseases to improve understanding of disease mechanisms.
        • Use gene modulation techniques (e.g., CRISPR/Cas or TALENs for genome editing) to conduct large screens for phenotypes relevant to arthritis and rheumatic diseases (see also Genetics and Genomics section for more information).
        • Create new animal models and use existing transgenic animals, and other genetically modified animal models, to study immune and inflammatory, as well as non-immunologic, mechanisms of arthritis and rheumatic diseases.
        • Combine animal models of human rheumatic diseases with systems biology approaches, to identify critical cellular and molecular pathways involved in disease causation, and to facilitate the identification of therapeutic targets. Possible areas include the central nervous system-endocrine-immune interactions that contribute to disease mechanisms and clinical symptoms.
        • Develop models for chronic (long-lasting) manifestations of disease (e.g., models to investigate the role of mast cells in chronically inflamed tissues).
        • Develop new and improve existing ex vivo tissue and organ models for studying arthritis and rheumatic diseases.
      2.  

      3. Therapy development

        Advances in immunology, molecular biology, and genetics are yielding an emerging set of therapies for arthritis and rheumatic diseases. The goal of NIAMS-supported research is to ensure a continuous supply of new targets for intervention, to understand the mechanisms of action of new and existing drugs, and to develop adequate clinical trial methodologies to test these mechanisms. The Accelerating Medicines Partnership, described in the box below, is one activity in which NIAMS is participating to ascertain and define shared and disease-specific biological pathways that researchers can study to identify relevant drug targets for the treatment of autoimmune diseases.

        Broad areas of potential research directions include:

        • Build on the successful treatment of rheumatoid arthritis with disease-modifying anti-rheumatic drugs, particularly early interventions to prevent progression to severe disease and tissue damage, toward the development of therapies for other arthritic and rheumatic diseases, e.g., lupus, scleroderma, ankylosing spondylitis, and other spondyloarthropathies.
        • Create therapeutic strategies to target immune dysregulation in arthritis and rheumatic diseases.
        • Develop approaches to prevent autoimmune diseases and promote immune tolerance (e.g., by screening for factors that promote desired immunological outcomes in B cells).
        • Explore tissue remodeling pathways involved in end organ damage to better understand pathophysiology and etiology of rheumatic diseases, and to identify new therapeutic approaches.
        • Foster pharmacogenetics and pharmacogenomics research to investigate the molecular basis of individual therapeutic response using robust genetic and genomic approaches.
        • Explore the integration of genetic and genomic analyses with the molecular and clinical diagnosis of disease in clinical care.
        • Improve patient stratification to enhance translational research studies including studies of remission, disease prevention and progression, and response to therapy.
        • Explore gene-based therapies including gene silencing (e.g., microRNAs, siRNA-conjugates, etc.) and overexpression approaches to treat or prevent disease.
        • Develop small molecule drugs targeting novel or known pathways.
        Accelerating Drug Development:

        To increase the number of new diagnostics and therapies for patients and reduce the time and cost of developing them, the NIAMS is participating in the Accelerating Medicines Partnership (AMP), a collaboration between the National Institutes of Health, the Foundation for the National Institutes of Health, the U.S. Food and Drug Administration, biopharmaceutical companies and non-profit organizations. The NIAMS is contributing to the AMP program in rheumatoid arthritis (RA) and lupus. The program uses emerging technologies to gain an enhanced systems-level understanding of gene expression and signaling in target tissues and cells from affected end organs (synovium for RA; kidney or other tissues such as skin for lupus) and peripheral blood. Results are expected to define shared and disease-specific biological pathways, which may lead to the identification of relevant drug targets for the treatment of RA, lupus and related autoimmune diseases. To realize the full value of the investment in the project, AMP data and analyses will be made publicly accessible to the broad biomedical community.

        For further information, see:

         

      4. Biomarkers

        The goal of biomarker research is to use modern approaches to discover and qualify biomarkers for the diagnosis, prognosis, and evaluation of therapies. In general, biomarkers are measured by changes in biochemical factors or genetic markers in blood, body fluids, or tissues. For many disorders, a panel of biomarkers rather than a single biomarker may provide the most clinically useful information.

        Broad areas of potential research directions include:

        • Identify changes in peripheral blood cells that correlate with activation of specific pathways in tissues during the course of arthritis and rheumatic diseases.
        • Develop organ-specific biomarkers to predict disease risk preclinically, and/or to monitor onset and progression of diseases.
        • Obtain an integrated data set of changes at the molecular level obtained by extensive profiling of gene expression and signaling in immune and tissue-resident cells.
        • Define and test algorithms in an appropriate population that integrate different sets of biomarker data (e.g., genetic, imaging, serologic, patient-reported) with sufficient power to facilitate personalized clinical decision-making regarding diagnostic tests, treatments, and prevention strategies.
        • Expand the use of autoantibodies as models for biomarker development to identify disease subtypes, and to track disease progression and therapeutic response.
        • Generate sensitive and reliable analytical methods coupled with assays that can detect multiple biomarkers "multiplex") in patient and control samples, to evaluate the complex systemic changes seen in rheumatic diseases.
        • Create resources needed to move promising biomarkers from the bench to the clinic using state-of-the-art statistical, analytical, and computational methods.
        • Develop validated and standardized outcome measures to enable a better assessment of biomarkers and the success of interventions.
      5. Imaging

        Imaging early or late changes of disease in target organs is increasingly important for characterizing disease status and determining responses to therapies. Advanced imaging technologies are providing insights into anatomic changes in disease states. For example, magnetic resonance imaging (MRI) has detected structural pathology in rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.

        Broad areas of potential research directions include:

        • Use and enhance intravital microscopy and improved fluorophores to gain new insights into cellular interactions and potential mechanisms of disease.
        • Enhance detection and quantitative measurements of structural pathology and inflammatory activity with MRI, ultrasound, optical or positron emission tomography (PET), for assessing arthritis and rheumatic diseases.
        • Apply modern high-sensitivity and high-resolution imaging techniques to the diagnosis of arthritis and rheumatic diseases.
        • Investigate the use of non-invasive imaging technologies in functional studies of disease prognosis and progression, potentially in association with biomarker qualification.
        • Develop novel imaging technologies to enable the analysis of soft tissues, including heart, blood vessels, kidney and the brain, to assess end-organ damage in rheumatic diseases.
        • Develop safer imaging approaches for clinical practice.
        • Develop ultrasound techniques (including 3D) to guide treatment decisions about inflammatory joint conditions.
    4. Arthritis and Rheumatic Diseases: Clinical Research

    5. The complexity of rheumatic diseases, diverse presentation and progression of many of these illnesses across patient populations, and the occurrence of multiple rheumatic diseases in the same patient, creates significant challenges in the diagnosis and management of these conditions. Clinical characterization of disease subtypes is critical to the assessment of epidemiological data and the efficient design of clinical trials. The NIAMS supports clinical research, ranging from epidemiological studies to observational studies to clinical trials, designed to further our understanding of these diseases and develop effective therapies to prevent or treat arthritis and rheumatic diseases.

      1. Epidemiology and health services research

        The incidence, morbidity, and mortality of rheumatic diseases are important foci for epidemiological research, particularly for studying complex, systemic autoimmune diseases and co-morbidities. Health services delivery for patients with rheumatic diseases is an important example of how illnesses with low mortality can still have significant physical and quality-of-life effects.

        Research needs and opportunities related to identifying mechanisms that would enable early detection and subphenotyping of autoimmune diseases were discussed in greater detail at a 2010 NIAMS roundtable discussion.

        Broad areas of potential research directions include:

        • Define and test preclinical strategies to understand disease pathways in humans to facilitate individualized screening and risk detection to prevent or treat early disease.
        • Combine analysis of the natural history of disease with population-based epidemiological studies to determine the prevalence of diseases and associated co-morbidities (e.g., cardiovascular disease).
        • Conduct research on ways to improve access to specialized care (especially for populations historically disadvantaged) and to facilitate patient-health care system interactions for improved disease outcomes.
        • Research the effects of patient-health care system interactions in disease outcomes.
        • Support efforts to leverage international partnerships and opportunities (e.g., cohort studies and registries) to improve diagnosis and treatment of rheumatic diseases.
        • Conduct research on environmental exposures that may contribute to the development of rheumatic diseases, including systems epidemiology research to investigate the exposome and integrate it with genomic, proteomic, and other “omics” datasets.
        • Conduct research to accurately identify individuals at high risk for autoimmune disease or those with very early-stage disease to facilitate clinical studies and trials to prevent or preempt the development of autoimmune disease.
        • Elucidate the role of the microbiome on risk, pathology and treatment of rheumatic autoimmune diseases.
        • Conduct research to understand the role of accelerated aging/immunosenescence on the pre-disposition, expression, and co-morbidities of rheumatic autoimmune diseases.
        • Focus prevention studies on risk-factor identification and reduction strategies, and conduct early intervention trials to prevent onset or progression of disease or tissue injury.
        • Explore the interactions between rheumatic diseases and common co-morbid conditions, such as atherosclerosis, obesity, and metabolic syndrome, to design effective risk management strategies, appropriate monitoring, and evidence-based early interventions.
        • Investigate the safe use of therapies, especially biologics, in pregnant women and their babies.
        • Develop computer models to assess the influence of prevention and treatment strategies on outcomes and cost-effectiveness in common chronic diseases (e.g., rheumatoid arthritis).
        • Apply computational tools and mobile health technologies to epidemiological studies of autoimmune diseases.
      2. Clinical trials

        Many rheumatic diseases do not respond adequately to treatment, particularly due to the diverse presentation and progression of these illnesses within a patient population, along with the complex interactions of biological pathways. Therapies that appear to be promising through preclinical modeling and testing require clinical testing in defined patient populations, or cohorts, and creative approaches to design the assessment of health outcomes. Recent advances in imaging technologies such as ultrasound, optical and magnetic resonance imaging, including 3D imaging approaches, also require testing in clinical trials to evaluate their use in diagnosis and patient care.

        Broad areas of potential research directions include:

        • Establish the role (qualification) of biomarkers and surrogates to diagnose, predict, or monitor disease progression and therapeutic response (efficacy and safety).
        • Employ large, systems approaches to disease modeling populated by well-defined phenotypes and qualified biomarkers, towards the development of more efficient clinical trial designs (by predicting cohort size) and more informed clinical decision-making (cost-effectiveness, potential toxicity vs. prevention, quality-of-life impact over time).
        • Determine whether drugs approved for rheumatic conditions can be repurposed to treat other rheumatic conditions with similar pathogenic pathways (e.g., drugs approved for rheumatoid arthritis in lupus, ankylosing spondylitis, or psoriatic arthritis).
        • Conduct proof-of-concept and bridging studies of approved and available therapeutics, to address clinically important questions in rheumatic diseases.
        • Investigate specific treatments and imaging approaches, including 3D modalities, for adult and pediatric rheumatic diseases.
        • Conduct research to improve outcomes for common disorders, such as gout, that are expected to worsen due to a number of factors affecting the population (e.g., aging, obesity).
        • Study the pharmacogenomics of responders and non-responders to pharmacologic and biological interventions in rheumatic diseases, in order to direct therapies to the appropriate subsets of patients.
        • Develop and test mechanism-based treatments (individual or combinations of drugs and biologics), strategies and/or models of rheumatic diseases that seek to prevent onset, induce remission (on or off medication), predict and address disease flare, and inform ongoing personalized treatments.
        • Develop, validate, and disseminate clinical outcome measures.
        • Conduct clinical studies to determine the benefits of treat-to-target-trials as compared to current strategies that focus on the level of disease activity.
        • Conduct studies to determine the optimal duration and intensity of treatment with FDA-approved drugs (e.g., disease-modifying anti-rheumatic drugs) or with novel therapies in development and explore the value of drug holidays and/or withdrawal of therapies.
        • Design clinical studies intended to better understand the onset, initiation, progression, improvement, remission and/or flaring of arthritic and rheumatic diseases in adults and children.
        • Conduct clinical trials related to the cause, prevention (e.g., vaccination to prevent herpes zoster), and treatment of system-specific pain.
        • Examine the effects of adding adjunctive treatments for co-morbidities (e.g., pain, fatigue, depression) to standard therapy for rheumatic diseases in patients with co-morbidities.
        • Examine the comparative effectiveness of therapies to address both the effectiveness and safety of therapies, and use combination therapy approaches for the treatment of rheumatic disease (e.g., compare the effectiveness of traditional therapies to biologic disease-modifying anti-rheumatic drugs in rheumatoid arthritis).
        • Explore alternative clinical trial designs for rare rheumatic diseases. Examples include active comparators rather than placebo controls, examples from cancer trials that have small cohorts, reassessed clinical research endpoints, and long-term clinical response.
        • Expand the involvement of clinical practice physicians in community settings in large-scale trials.
    6. Arthritis and Rheumatic Diseases: Behavioral and Biopsychosocial Research

      Understanding the etiology, pathogenesis, and outcomes of rheumatic diseases, and developing effective strategies for their prevention and treatment, requires a multifaceted approach. These endeavors necessitate collaborative research efforts that integrate approaches and perspectives from multiple disciplines.

      Biomedical research in the rheumatic diseases continues to yield important discoveries regarding genetic, immunologic, and other biological factors in these conditions. Behavioral and social science research is contributing important epidemiologic information and approaches to managing the distressing symptoms of these disorders (see box below). However, studies integrating behavioral, basic biomedical, and clinical rheumatology perspectives have been extremely limited to date. The potential of the behavioral and social sciences and a biopsychosocial approach to advance research in the rheumatic diseases has not been fully realized. Recognizing the need for collaborations to advance behavioral and biopsychosocial research, the NIAMS participates in a number of relevant trans-NIH efforts (e.g., the NIH Pain Consortium and the National Center on Sleep Disorders Research) which allows the Institute to share information about NIAMS-funded research efforts and advances and to partner with other NIH components in areas of interest. Interdisciplinary investigations that integrate behavioral and biomedical sciences will likely enhance treatment of rheumatic diseases, reduce disability, and may shed light on the complex mechanisms involved in disease processes.

      Research needs and opportunities were discussed in 2010 at a roundtable on Psychosocial and Behavioral Therapies for Musculoskeletal and Rheumatic Disease Outcomes.

      1. Behavioral

        Broad areas of potential research directions include:

        • Define genetic and environmental influences on behaviors relevant to health and disease.
        • Explore cognition and cognitive dysfunction in rheumatic diseases, including the use of brain imaging and assessment of relationships between cognition, mood disturbance, and disease activity.
        • Generate theoretical models for the potential influence of stress on disease course and presentation (e.g., symptom flares). Research the influence of stress management techniques and interventions on illness, and study potential mechanisms of stress-illness effects.
        • Study fatigue in the rheumatic diseases, focusing on epidemiological issues, potential mechanisms, prevention, and treatment.
        • Investigate sleep disturbances and their relationship to disease process, symptoms, and disability in rheumatic diseases.
        • Develop animal models to elucidate behavioral mechanisms in rheumatic diseases.
        • Use mobile health technologies (e.g., smart phones) to facilitate research on the role of behavioral factors in rheumatic diseases.
      2. Psychosocial

        Broad areas of potential research directions include:

        • Study the biological, social, and behavioral interactions as they relate to disease onset, progression, and outcomes.
        • Define the effect of systemic and societal influences on disease progression, treatment response, quality of life, and other patient-reported outcomes in rheumatic diseases.
        • Study the variability in patient outcomes, symptom perception and management, and interactions with health-care systems, related to differences in behavior, gender, ethnicity, family environment, prior trauma, education, physiology, or a combination of factors.
        • Explore behavioral factors that influence patient interactions with providers, and how this experience affects treatment response and long-term outcomes.
        • Examine psychosocial prevention and intervention models from other disorders (e.g., diabetes, AIDS), for the promotion of healthy behaviors and management strategies for people/patients with rheumatic diseases.
        • Address issues in pediatric rheumatology, including pain, psychosocial adjustment, physical functioning, and intervention.
        Patient-centered Outcomes:

        Patient-centered outcomes (PCO) such as patient-reported outcomes (PRO) are keys to better treatment and understanding of rheumatic diseases and their impact on patients’ symptoms, functioning and quality of life. Most PCO instruments have traditionally been used for disease-specific assessments, rather than to facilitate within, or across, disease comparisons. Although PROs are very popular among patients, often the patient concerns and their rankings of what matters most may be very different from the outcomes that physicians seek. The NIH Common Fund's Patient-Reported Outcomes Measurement Information System (PROMIS) initiative was created to address these gaps by the development and validation of a psychometrically-robust PRO instrument to gather information on many health-related concerns, such as pain, fatigue, and physical functioning, across a wide range of disorders. This information will be used to assess symptoms, and to measure changes over time and in response to treatment. The component questions of the PROMIS instrument undergo rigorous testing in culturally and ethnically diverse populations, with a particular focus on the individual use of language to describe PROs. A wide variety of adult and pediatric (including parent proxy) PROMIS instruments are available for use in clinical trials, point-of-care visits or large scale surveys.

         

      3. Therapies

        Broad areas of potential research directions include:

        • Conduct studies on the management of chronic symptoms, such as itch, fatigue, pain, and stress.
        • Integrate patient-reported outcomes and clinical measures to support medical decision-making and improve quality-or-life for patients with chronic conditions.
        • Investigate placebo responses to pain and treatment, and the impact of catastrophizing and individual pain experiences in disease management and treatment response.
        • Explore integrative and complementary therapies, such as biofeedback, relaxation, mind-body interactions, cognitive behavioral therapy, and exercise.
        • Investigate the role of non-pharmacological treatments and combined individual, group, and technology-based interventions for the self-management and improvement of health-related behaviors.
        • Investigate the use of behavioral interventions (e.g., diet, dietary supplements, various forms of exercise) to manage disease symptoms or prevent disease progression.
  2. SKIN BIOLOGY AND DISEASES

    The Skin Biology and Diseases programs at the NIAMS cover basic, translational, and clinical research in skin, including a variety of both common and rare skin diseases. The programs include investigations on the molecular, cellular, and developmental biology of skin as well as the study of skin as an immune, sensory, endocrine and metabolic organ. Wound healing, autoimmune, inflammatory, and heritable diseases, and birth defects are also in the programs. The goal is to translate fundamental research findings into novel diagnostic tools, effective therapeutics, and efficient, cost-saving disease management.

    Understanding skin biology in the context of whole body physiology is a new horizon. Skin is an integral part of the human body, thus skin function and diseases are influenced by both the internal and external environments. Increasing evidence suggests that skin homeostasis is modulated by the immune, nervous and endocrine systems, as well as circadian rhythms and the resident microbial flora. Studying interactions between skin and other organs is increasingly important, involving multidisciplinary collaborations, thus invigorating and enriching the skin research field.

    1. Skin Biology and Diseases: Trans-discipline Basic Studies

      Advances in basic research on skin biology have been the foundation to improve cutaneous health in the past hundred years. Basic research will continue to be the driving force for innovation in combating diseases that affect the skin, hair and nails including specific regions of the skin such as the scalp, and areas of skin rich in skin appendages.

      1. Skin molecular and cell biology

        Broad areas of potential research directions include:

        • Investigate chromatin structure and epigenetic mechanisms.
        • Study transcriptional, co-transcriptional and post-transcriptional regulatory mechanisms.
        • Study non-coding RNA regulatory networks.
        • Study the mechanisms of cell division, proliferation and differentiation.
        • Identify novel mechanisms in cellular movement, sensing, intracellular transportation, and secretion.
        • Develop new or improved technologies to isolate and characterize single cells and small populations of cells from skin.
        • Investigate the interactions between the skin and other organ systems, as well as the systemic effects of perturbations in skin homeostasis.
        • Define regulatory networks in gene regulation and cellular communication.
      2. Stem cells

        Skin function is developed and maintained by a variety of stem cells (e.g., keratinocyte stem cells, hair follicle stem cells, melanocyte stem cells, sebaceous gland stem cells, mesenchymal stem cells, etc.). Understanding skin stem cells is a key research area. Broad areas of potential research directions include:

        • Define stem cell populations in the skin, determine the regulatory mechanisms that control self-renewal and lineage commitment, and elucidate the role of these cells in skin development, homeostasis, and diseases.
        • Define the location, components and properties of the stem cell niches, and how these niches maintain the stem cell population.
        • Define stem cell developmental potential (pluripotency), progeny heterogeneity, and the possibility of inter-lineage conversion via dedifferentiation.
        • Map cellular lineages in the skin and determine how different cell types/subtypes interact with each other, and the importance of these interactions on development, homeostasis, and disease.
        • Explore the use of induced pluripotent stem (iPS) cell technology as a tool of research and a modality of therapy.
      3. Developmental biology
        • Understand the development of mammalian skin.
        • Define specific genes and regulatory pathways in the development of skin and its appendages, including the use of cell type-specific knockouts and overexpression.
        • Define and understand the regulatory signals (cytokines, growth factors, morphogen gradients, etc.) that shape the skin as an organ.
        • Elucidate interactions between components of the dermis and epidermis during development.
    2. Skin Biology and Diseases: Skin as a Barrier

      The primary function of skin is to provide a physical barrier, which is flexible, resilient to mechanical force, properly sealed, capable of blocking UV radiation, with regional specializations to accommodate movement, pressure and friction. The barrier is also biological, keeping microbial flora in check and repelling their infiltration. Defects in skin barrier structure and function are a major cause of disease.

      1. Keratinocytes (epidermis)

        The keratinocyte is the major cell type that forms the outer physical barrier of the body. It also contributes to the immune and sensory functions of the skin.

        Broad areas of potential research directions include:

        • Delineate the differentiation pathways of keratinocytes in vitro and in vivo, to improve understanding of skin diseases, to identify potential therapeutic targets, and to guide the transformation of iPS cells into differentiated keratinocytes.
        • Investigate the structure and function of the protein complexes that maintain the structural integrity of the epidermis—such as desmosomes, hemidesmosomes, and the cytoskeleton—and the related genetic defects that contribute to the pathogenesis of pachyonychia congenita, forms of epidermolysis bullosa, and other diseases.
        • Explore the structure and function of the skin permeability barrier (the stratum corneum), and how it changes with skin aging and disease.
        • Identify targets for therapies to restore normal barrier function in disease and conditions such as premature birth.
        • Determine how changes in the skin barrier in injured or diseased skin affect drug concentrations in the skin during topical therapy.
        • Study epidermal function as a barrier to transported molecules to inform the development of delivery methods for topical agents.
        • Determine the role of circadian rhythms on barrier function.
        • Investigate the role of keratinocytes in skin immune and sensory functions.
      2. Skin photobiology and melanocytes

        Electromagnetic radiation, visible or invisible, has many effects on normal and pathological skin physiology. As a primary shield of this radiation, melanocytes possess unique properties to protect vital stem cells and subcutaneous tissues. Pathological conditions affecting melanocytes can lead to hyper- and hypopigmentation of skin that can significantly affect patients’ quality of life.

        Broad areas of potential research directions include:

        • Study the effect of electromagnetic radiation on skin biology (e.g., activation of melanin synthesis, vitamin D synthesis and immunosuppression).
        • Investigate melanocyte lineage development (see also Stem cells).
        • Investigate melanocyte proliferation, differentiation, and population heterogeneity.
        • Study pigment synthesis and transport pathways.
        • Improve understanding of interactions of melanocytes with other cell types, especially with the cells of the immune system in the development of vitiligo.
        • Explore melanocytes’ role in the overall skin photobiology.
        • Identify molecular and genetic differences between pre-neoplastic nevi and senescent nevi that do not develop into invasive melanomas.
        • Identify the genetic and molecular basis of inherited pigmentation disorders, such as oculocutaneous albinism.
      3. Fibroblasts and extracellular matrix

        Basement membrane and dermis provide much of the structural support and mechanical strength of the skin barrier. The role of extracellular matrix in regulating cytokine activity and cellular behavior has just begun to be appreciated. A major focus of research in this area is how fibrosis develops.

        Broad areas of potential research directions include:

        • Investigate the biology of normal fibroblasts and their myriad variations (e.g., trans-differentiation to myofibroblasts) during normal and diseased physiology; the latter may lead to excessive deposition of extracellular matrix, such as in sclerosis and fibrosis.
        • Identify and characterize subpopulations of fibroblasts in the dermis, including developmental origins, roles in skin homeostasis, and contributions to repair after injury.
        • Define dermal fibroblast diversity in different body sites, to understand the cell types involved in skin diseases that preferentially affect distinct parts of the body (in conjunction with skin innervation patterns; also see Skin as a Sensory and Endocrine Organ).
        • Elucidate the interactions between epidermal and dermal components that are crucial for normal processes such as hair follicle development and hair cycling, and define the role for these interactions in diseases.
        • Research the biology of adipocytes, including their roles in skin homeostasis, repair after injury, and disease.
        • Study the mechanisms that regulate the normal assembly, interactions, and function of the molecular components of the extracellular matrix (ECM) (e.g., collagens, fibrillins, matrix metalloproteinases).
        • Study the regulatory function of the ECM (e.g., in cytokine bioavailability).
        • Study ECM-cell interactions (e.g., via integrin).
        • Understand the mechanisms of ECM diseases (e.g., scleroderma, Marfan syndrome, Ehlers-Danlos Syndrome, dystrophic and junctional epidermolysis bullosa, pseudoxanthoma elasticum)
      4. Vasculature

        Broad areas of potential research directions include:

        • Expand our understanding of the mechanisms controlling angiogenesis, lymphatic genesis and the structure and function of lymphatic/blood vessels in normal skin development.
        • Investigate and understand the cellular/molecular/genetic biology of skin vasculature that cause cutaneous vascular malformations or affect angiogenesis in chronic wounds, inflammatory, fibrotic and psoriatic diseases.
        • Understand the cause of and develop therapies for skin vasculature birth defects (e.g., hemangioma and port wine stain).
      5. Breach of the barrier

        Barrier defects and wounds can lead to a variety of skin diseases. Barrier leakage can cause excessive loss of water and other small molecules, or increased infiltration of environmental substances including microorganisms that lead to skin immune reactions. More severe disruption of the skin barrier triggers a wound healing response, which is a complex process, shaped during evolution to ensure rapid restoration of tissue integrity, by coordinating the activity of a large repertoire of cell types involved in covering the wound bed, fighting microbial infection and rebuilding the tissue architecture. Wound healing studies are therefore inherently multidisciplinary.

        Broad areas of potential research directions include:

        • Study the molecular basis of barrier leakages and their consequences.
        • Study the relationship between barrier defects and skin immune reactivity.
        • Understand how the wound healing response is initiated and terminated.
        • Define the minimal injury, at the molecular level, that triggers the wound healing response.
        • Understand the process by which such injury is detected.
        • Study basic mechanisms of wound healing, such as stem cell activation, cell identity change, cell migration, differentiation, ECM remodeling, angiogenesis and the control of inflammation.
        • Study the role of the macrophage in wound healing, particularly its regulatory and coordinating function in orchestrating the progression of healing and the process of rebuilding tissue.
        • Study the role of systemic/mesenchymal stem cells (e.g., bone marrow derived) in skin wound healing.
        • Understand interactions of multiple systems, factors and pathways, such as interactions among components of epithelia; endothelia; mesenchymal, immune, and inflammatory cells; and connective tissue.
        • Research the milieu of slow-healing and chronic wounds to identify the factors that impair the healing process. These include microbial populations, hypoxia, inflammatory cytokines, cellular dysregulation and other physical and chemical properties of the chronic wound.
        • Define the molecular and genetic mechanisms in aberrant/exuberant wound healing that lead to fibrosis or scar/keloid formation. The relationship between wound healing and fibrosis is intriguing. Fibrosis is invariably triggered by injury, hence is intrinsically related to the healing process.
        • Explore the role of extracellular matrix remodeling in normal wound healing and diseases (e.g., chronic wounds, keloids), and the effects of ectopic mineralization.
    3. Skin Biology and Diseases: Skin as an Immune Organ

      The skin is not only a major physical barrier, but also is a complex neuro-immune organ densely coated by microbial communities, and populated by keratinocytes and resident immunocytes that, in combination, provide a robust immunological barrier to potential insults. In response to invading pathogens, microbial commensals, keratinocytes and immunocytes conjointly ne utralize invaders and subsequently restore skin homeostasis. Failure to restore skin homeostasis may be associated with microbial dysbiosis and deregulated cutaneous innate and/or adaptive immunity, resulting in inflammatory and/or autoimmune skin diseases. An example of a recent discovery in this area is featured in the box below.

      Understanding Atopic Dermatitis (AD):

      A recent study suggests that δ-toxin, a protein produced by S. aureus, promotes the allergic skin reaction observed in individuals with AD. Because activation of mast cells is known to play a role in AD, researchers tested the effects of S. aureus toxins on mast cells grown in the laboratory. They found that δ-toxin activates mast cells not only in the laboratory, but also when injected into the skin of mice. Previous research has shown that an antibody, immunoglobulin-E, or IgE, also triggers the activation of mast cells in AD. The researchers investigated whether the δ-toxin and IgE use the same processes to trigger mast cell activation. Although δ-toxin worked synergistically with IgE in the activation of mast cells, results showed that the two molecules exert their effects via slightly different mechanisms. To determine whether δ-toxin promotes allergic skin disease, the researchers infected a mouse model that is susceptible to allergic skin disease with S. aureus. The mice developed AD like lesions at the sites where the bacteria were applied. The δ-toxin produced by S. aureus and enriched in lesional skin of patients with AD, was identified as a potent inducer of mast cells degranulation. In addition δ-toxin has the ability to synergize with IgE in the activation of mast cells. This study helps to understand the mechanism by which a factor released by microbes collected in lesional skin of patients with AD activates resident immune cells and exacerbates skin allergy in mice.

      Reference:
      Nakamura Y, et al. Nature. 2013. PMID: 24172897

       

      1. Immunobiology of the skin

        Keratinocytes continuously screen their microenvironment and rapidly respond to signals by expressing pro-inflammatory cytokines, chemokines and anti-microbial peptides (AMPs). In addition, keratinocytes can initiate adaptive immunity by presenting foreign antigens to resident skin memory and effectors T cells. Multiple other types of immunocytes, such as langerhans cells (that reside in the epidermis and constantly sense the microbiome), dermal dendritic cells, macrophages, monocytes, eosinophils, mast cells, and innate lymphoid cells screen the external microenvironment, the epidermis and/or the dermis. Overall, these immunocytes regulate and are key effectors of innate and adaptive skin immune responses against invading pathogens and/or tumors. Importantly, microbial commensals help the skin immune system to mature and release factors such as AMPs that antagonize pathogen invaders. On the other hand, the skin is “wired” by the nervous system, and researchers are investigating the mechanisms by which the skin immune and nervous system communicate. Findings focused on the regulatory role of microbial commensals, keratinocytes and immunocytes and their expressed factors, such as cytokines, chemokines, microbial and keratinocyte AMPs and neuropeptides, have opened new avenues for the understanding of the immunobiology of healthy and diseased skin.

        Broad areas of potential research directions include:

        • Study the skin as an active immune organ, focusing on keratinocytes and immunocytes (such as resident memory αβ-T cells or γδ T cells) that reside in and traffic through skin, as well as their receptors and soluble factors. Appropriate tools include animal models, human tissues, single-cell analysis, three-dimensional cultures and real-time in vivo imaging technologies. Studies demonstrating the relevance of observations in mouse models to human disease are also needed.
        • Develop in vivo and in vitro models to define key regulatory signaling pathways activated in human keratinocytes and/or immunocytes by chemical insults, skin tumors, resident skin commensals and/or invading pathogens using novel reagents and techniques (such as novel immune profiling tools).
        • Discover new mechanisms by which keratinocytes and immunocytes interact and synergize. Characterize the mechanisms by which skin immunocytes affect hair follicle biology.
        • Phenotype the microbiome in healthy and lesional skin, and define the bidirectional molecular signals that skin microbial communities use to communicate with each other and with the cutaneous immune system.
        • Define how changes in the skin barrier affect microbial communities on the surface of the skin and their access to the dermal compartment.
        • Define the mechanisms by which resident microbial flora influence the development and function of the skin as an immune organ.
        • Investigate the host genetic factors that control establishment of the microbiota.
        • Define the mechanisms by which the resident microbiota of the gut, lung, oral cavity and other mucosa affect the skin resident microbial communities, as well as how the skin microbiota affects microbial communities in mucosal body sites.
        • Understand the molecular basis by which the cutaneous immune and the systemic immune systems influence each other.
        • Develop models aimed at defining the molecular basis by which the cutaneous immune system and the nervous system communicate in healthy and diseased skin.
        • Understand the molecular basis by which the cutaneous immune and the coagulation systems interact to regulate skin inflammation.
        • Understand how endocrine signals from the skin regulate skin immunobiology.
        • Develop imaging and nanotechnology approaches for studying skin structure in situ trafficking, and interactions of immune cells in skin.
        • Analyze the influences of subcutaneous adipocytes and corresponding lipid metabolism in the regulation of skin immune functions.
        • Develop in vivo models to define the mechanisms by which the circadian clock regulates skin immunobiology and homeostasis.
        • Define the role of the immune system in the initiation, development, and surveillance of skin cancer.
      2. Inflammatory and immune skin diseases

        Samples of skin are readily accessible and skin is the primary target organ of many inflammatory and autoimmune diseases. These characteristics facilitate the implementation of systems biology approaches to skin disease research that defines functional signatures (e.g., activated cellular subsets, differentially regulated genomics, epigenomics, transcriptomics, and proteomics, antibody and receptor repertoires, signal transduction pathways, metabolomics and the microbiome). Novel bioinformatics tools and infrastructure are needed to advance research on the mechanisms by which these functional signatures are combined to contribute to pathogenesis in specific diseases.

        Genome-wide association studies and deep genome-wide sequencing studies are yielding important results for complex skin disorders, such as atopic dermatitis, psoriasis, alopecia areata and vitiligo. Yet, the majority of the genetic signals associated with psoriasis, and other immune-mediated diseases do not fall in known gene-coding regions. Efforts such as the NIH ENCODE (Encyclopedia of Coding DNA Elements) are generating the data needed to accurately co-localize risk loci. On-going functional genomics studies are identifying key molecular and cellular pathways and are revealing important insights into disease mechanisms that may lead to the development of treatments.

        1. Genetic and epigenetic studies of skin immune diseases

          Research is needed to improve understanding of disease risk and pathogenic pathways that contribute to complex disease pathogenesis. Integration of information obtained from GWAS, deep genome-wide sequencing studies, ENCODE, chromatin structure and epigenetic markers data and functional genomic studies will advance understanding of skin immune diseases.

          Broad areas of potential research directions include:

          • Integrate data from functional and mechanistic studies, proteomics, microbiome and metabolomics signatures with common and rare risk loci found by genetic and genomic approaches, to investigate the relationship between genotype and phenotype, and to understand pathogenic mechanisms and disease progression.
          • Utilize public data on the functional elements of the human genome, available from the ENCODE Project, the NIH Roadmap Epigenomics Project, and other sources, to prioritize coding and non-coding disease risk variants and develop mechanistic hypotheses for follow-up functional studies. Generate similar data for the many cell types in skin and make these data broadly available.
          • Investigate how common and rare variants identified using genomics approaches contribute to disease pathogenesis through functional genetic studies in animal and in vitro model systems.
          • Study the roles of gene-environment interactions, epigenetics, non-coding regulatory DNA, chromatin interactions, and other modifiers of gene expression (e.g. microRNAs, lncRNAs) in disease pathogenesis.
        2. Pathogenesis Studies

          Discover innate and/or adaptive cellular and molecular mechanisms that trigger, regulate and control inflammatory and autoimmune conditions such as pemphigus, pemphigoid, psoriasis, psoriasis arthritis, atopic dermatitis, alopecia areata, cicatricial alopecia, vitiligo, acne, rosacea and others.

          Broad areas of potential research directions include:

          • Define specific innate or adaptive signaling pathways that can be targeted to treat inflammatory and autoimmune skin diseases. Define shared and convergent innate or adaptive signaling pathways than can be targeted in more than one inflammatory and autoimmune skin disease.
          • Examine the deep sequencing of antibody repertoires in pemphigus and pemphigoid, and characterize the autoantibody repertoires that define self and foreign antigens. Explore the mechanisms by which autoantibodies cause blistering of the skin in the immunobullous diseases, to inform the development of drug therapies.
          • Study the role of the skin microbiome as a potential trigger and regulator for autoimmune and inflammatory diseases of skin.
          • Assess how the microbiome may serve as a biomarker to predict the outcome of skin diseases. Define the impact of dysbiosis on healthy immune function and its contribution to inflammatory and autoimmune disorders of the skin.
          • Investigate the role of the inflammasome and other modulators of inflammation in skin diseases.
          • Investigate innate and adaptive signaling pathways contributing to disease co-morbidities, such as cardiovascular disease, metabolic syndrome and diabetes.
          • Use novel epidemiology methods to link skin diseases with systemic co-morbid conditions.
          • Discover triggers of inflammation and autoimmunity. Investigate single or shared mechanisms involved in the onset, development and progression of these diseases.
          • Characterize altered lipid metabolomics and glycolysis pathways leading to inflammatory and autoimmune skin diseases.
          • Investigate how efficacious drugs affect cellular metabolism.
          • Investigate the mechanisms by which the circadian clock affects immune mediated skin diseases. Delineate the immune mechanisms underlying the common symptom of itching.
    4. Skin Biology and Diseases: Skin as a Sensory and Endocrine Organ

      Skin is the body’s largest interface with the immediate external environment, being exposed to myriad physical, chemical and biological agents and stimuli. Thus, skin has evolved into a sensory organ and an outreach of the nervous and immune systems to assess and interact with the external environment. Skin is also an endocrine organ, known as a site of hormone synthesis, and capable of communicating with the rest of the body via multiple endocrine pathways.

      Research needs and opportunities related to itch were discussed in greater detail at a 2010 NIAMS roundtable discussion.

      Broad areas of potential research directions include:

      • Study of skin innervation.
      • Define the sensory functions of resident skin cells (e.g., keratinocytes, Merkel cells, components of the hair follicle).
      • Study the mechanisms of itch and pain and define their mediators in the skin under normal and pathological conditions.
      • Study the mechanisms of touch and temperature sensation.
      • Investigate the interactions among skin sensations, i.e., itch, pain, touch and temperature.
      • Develop therapeutic methods to control itch and pain in disease conditions.
      • Investigate the role of skin innervation in normal tissue and in pathological conditions such as inflammation and chronic wounds.
      • Understand skin’s endocrine function.
      • Investigate the circadian regulation of skin physiology.
      • Understand the mutual influence of psychology (i.e., mind) and skin biology (i.e., body) under normal and pathological conditions.
    5. Skin Biology and Diseases: Skin Appendages

      Skin appendages, (e.g., hair, nail, sebaceous glands and sweat glands) provide many of the auxiliary functions of skin. Compared to the epidermis, these epithelia-derived mini-organs/tissues are understudied. An exception is hair/hair follicle, which has proven to be a very powerful model for understanding tissue/organ development and regeneration.

      Broad areas of potential research directions include:

      • Study the development and maintenance of skin appendages.
      • Identify potential stem cells and their niches.
      • Understand the function and regulation of stem cells in normal skin and in pathological conditions.
      • Investigate the etiology of diseases related to skin appendages.
      • Understand the regenerative potential and condition of skin appendages.
    6. Skin Biology and Diseases: Genetics of Skin Diseases and Birth Defects

      Many, if not all, aspects of skin function are known to be affected by genetic mutations, producing a spectrum of clinical manifestations ranging from minor, cosmetic, irritant, (deteriorating quality of life) to fatal. The genetic factors affecting skin conditions can be monogenic or polygenic, including sequence variations in protein coding DNA, as well as noncoding regulatory regions functioning through genetic and epigenetic mechanisms. A large repertoire of therapeutic modalities are employed or being considered to combat heritable skin defects with known or unknown etiology (also see Therapy Development).

      Broad areas of potential research directions include:

      • Discover new genetic bases of skin diseases.
      • Discern the genetic and environmental contributions in skin birth defects.
      • Understand the process by which genotype is translated into phenotype.
      • Define the modifier genes and the effect of genetic background on phenotype heterogeneity (e.g., disease risk/severity assessment).
      • Identify the genes that contribute to defects in the skin barrier, both in common skin diseases such as atopic dermatitis, as well as in rare inherited disorders where studies of pathogenesis may inform our understanding of the common diseases.
      • Define and characterize the biochemical and cellular networks affected by the mutations underlying skin diseases.
      • Understand the mechanisms of spontaneous reversion of disease phenotype in some genetic diseases, and explore their therapeutic potential.
      • Build genetic and epigenetic databases relevant to skin biology and skin diseases.
      • Conduct genome-wide association studies to discover co-morbidities of skin diseases and understand shared pathways.
      • Apply high-throughput genomic and epigenomic technologies, combined with mathematical and bioinformatics methodologies, to elucidate the regulatory networks involved in normal skin biology and disease states.
      • Investigate the function of noncoding RNAs, including microRNAs and long noncoding RNAs (lncRNAs), in skin development and diseases.
      • Study the genetic basis of heritable defects in skin development, known collectively as ectodermal dysplasias, to provide insights into the regulatory pathways that are critical for the development of skin and its appendages.
    7. Skin Biology and Diseases: Regenerative Medicine

      Regeneration mimics the embryonic process that shapes the original tissue, therefore it heals injury without the scarring and functional deficits associated with repair, which relies on “makeshift” material (substitute) to close the wound (rapidly). Treatment of large area acute skin wounds, such as extensive burns and trauma, requires both processes, and the present challenge lies in how to restore tissue function after the wound is closed. Regenerative medicine in skin involves research on developmental processes, epigenetics, the skin microenvironment, and engineering approaches to create temporary tissue substitutes or modify wounds to facilitate healing and functional restoration. Regeneration research advances understanding of adult organ neogenesis, which helps fully restore tissue function, and also includes the development of engineered living skin, seeking to mimic the native organ.

      1. Skin embryonic development
      2. The concept and practice of regenerative medicine are firmly rooted in the study of developmental biology. Knowledge of developmental biology principles in skin provides important insights into tissue regeneration. Studies of hair follicle neogenesis have revealed that adult skin may possess more regenerative capacity than previously thought. (See also Developmental Biology)

        Broad areas of potential research directions include:

        • Apply the principles of skin and skin appendage development to the regeneration of normal skin in vivo following injury.
        • Apply knowledge of skin and skin appendage development to engineering of replacement skin in the lab.
      3. Tissue neogenesis
      4. Broad areas of potential research directions include:

        • Understand skin’s regenerative potential.
        • Define conditions that induce adult neogenesis or hinder it.
        • Discover mammalian model systems that can regenerate skin and appendages, virtually restoring full function (such as African spiny mouse).
        • Develop methods for the in vivo tracking of exogenous (e.g., transplanted) cells in regenerative medicine applications, to determine if they play only a transient role, or whether they become permanently incorporated into regenerated tissue.
      5. Engineered skin tissues
      6. Broad areas of potential research directions include:

        • Develop a new generation of skin equivalent that can better mimic natural skin functions, e.g., vasculatures, immune functions, pigmentation, innervations, etc.
        • Develop modular skin 3-D models that can interact with other organ models to study integrated human physiology (e.g., as proposed in the NIH Common Fund’s Integrated Microphysiological Systems initiative).
        • Explore the use of iPS cells in engineered skin.
        • Explore the use of natural ECM components as biomaterials that provide appropriate structural and mechanical properties for generating functional skin. Develop biomaterials and scaffolds that mimic or result in functionally superior ECM.
        • Develop wound coverings for drug/growth factor delivery to promote healing and regeneration.
    8. Skin Biology and Diseases: Technology and Instruments

      The accessibility of skin as an organ provides unique opportunities for developing technology for real time, in vivo, non-invasive means of observation and intervention. Broad areas of potential research directions include:

      • Develop intravital microscopy technologies that allow the analysis of the behavior of cells in their native environment and in real time, and adapt these technologies to the study of human skin.
      • Develop instruments to measure non-invasively the physical, mechanical and chemical properties of skin.
      • Develop tracers and reporters for cell tracking, lineage tracing, and for monitoring the biochemical processes in the skin.
      • Develop photo/light sensitive probes for manipulating cellular and biochemical events in vivo.
    9. Skin Biology and Diseases: Model Systems

      In biomedical research and therapeutic development, hypotheses and drugs must be evaluated in model systems. These can be living organisms or in silico equations.

      1. Animal models

        Genetically modified organisms and many naturally occurring mutant strains are powerful tools for current research Still, finding suitable models to address specific questions in skin research remains challenging. One recurring issue is whether findings in the mouse model can be directly translated into understanding human biology. The pig has been regarded as a better model than other animals for skin studies primarily because pig skin more closely resembles that of humans. The transplantation of human skin to a mouse, or reconstituting the human immune system in a mouse, may be useful for investigating some human skin diseases. Complex diseases are likely to be modeled with transgenic mammals, and some polygenic diseases (e.g., alopecia areata) have emerged spontaneously in mice and other large animals, such as dogs and monkeys. On the other hand, research in small vertebrates (fish), invertebrates (fly and worm), and other lower organisms is advantageous because researchers can examine large numbers of them using high-throughput technology.

        Broad areas of potential research directions include:

        • Develop animal models to study the role of specific genes and regulatory pathways on the development of skin and its appendages, as well as on skin homeostasis.
        • Generate and validate animal models that mimic human skin diseases, including grafting of human skin onto mice to examine molecular and cellular processes in a controlled experimental environment.
        • Utilize new gene editing technologies (e.g., CRISPR/Cas, TALENs) to create animal models of human heritable skin diseases for studies of disease pathogenesis and testing of new therapeutic agents.
        • Explore the use of zebrafish, fly, and other genetically tractable model organisms for modeling skin diseases and mutations, and for high-throughput genetic screening.
        • Develop animal models to study the role of the skin microbiota in skin health and disease.
        • Generate animal models to investigate the mechanisms of tissue damage by toxic industrial chemicals and chemical threat agents, and for testing the efficacy of potential countermeasures.
        • Conduct research using human skin transplants and patient-derived or genetically engineered human skin equivalents, and reconstitution of the human immune system.
        • Combine genetically engineered animal models and intravital imaging to study the trafficking of cells (e.g., immune cells) in live skin, and to visualize specific cell populations such as stem cell subpopulations and their progeny.
      2. In vitro cell-based models

        Cultured skin substitutes and other in vitro models of skin are in current use, particularly for toxicology screening.

        Broad areas of potential research directions include:

        • Develop 3D tissue models of normal human skin and of skin diseases.
        • Use patient-derived iPS cells and gene editing technologies to create disease models to study the roles of specific genes and pathways in disease pathogenesis, as well as to test therapeutic agents for personalized medicine approaches.
        • Develop efficient, highly reproducible, and scalable protocols to produce differentiated skin cell types from iPS cells, characterize these differentiated progeny using functional assays and genomic technologies, and compare to cells in vivo.
        • Explore direct reprogramming of adult somatic cells as an alternative strategy to generate skin cells for in vitro models and for cell-based therapies.
        • Develop in vitro models to study host-microbe interactions in the skin.
      3. In silico modeling

        Systems biology is a research approach used to understand the network behavior of biological systems, in order to predict the effect of perturbations in the system or to develop novel ways to modulate the system's behavior. In systems biology modeling, conceptual and mathematical models are developed and trained by test data and then used to predict the behavior of real biological systems. To facilitate the development of a successful systems model, it is critical to attain consensus on standards for collecting and reporting research results.

        Broad areas of potential research directions include:

        • Model regulatory networks of genes, proteins, and cells in skin.
        • Encourage collaboration between biologists and mathematicians to enable the use of systems biology approaches to model complex biological systems.
        • Develop disease models (virtual patients) to inform clinical trial design and clinical practice.
        • Enhance training in computational biology and bioinformatics.
    10. Skin Biology and Diseases: Therapy Development

      Knowledge of pathogenic pathways, as well as basic skin biology, allows the development of small molecule and biologic therapies (e.g., antibodies) that target specific components of these pathways. These approaches facilitate effective and systemic treatment with minimal side effects, which is often required for widespread skin lesions. Because of the accessibility of skin, treating diseases of the skin, hair and nails, including diseases of the scalp and of skin appendages is not limited to chemical intervention; physical methods have also been explored.

      Needs and opportunities related to therapies for pediatric dermatologic disease were discussed in 2011 at a NIAMS roundtable.

      Broad areas of potential research directions include:

      • Translate gene-based discoveries into novel therapeutics.
      • Exploit drug repurposing for skin therapeutics.
      • Discover small molecular activators and inhibitors of cellular processes as potential therapeutic agents.
      • Study the pharmacogenomics of responders and non-responders to pharmacologic and biological interventions in skin diseases, in order to direct therapies to appropriate subsets of patients.
      • Develop interventions that reverse, not merely delay, the adverse changes that occur in aging skin.

       

      1. Gene and cell-based therapy

        For monogenic skin diseases such as epidermolysis bullosa (EB) simplex (see box below), there is the possibility of correcting the defective gene. One possible approach would be to use CRISPR/Cas technology in combination with iPS cells, thus addressing the root cause of the disorder. Another approach, being tested for patients with EB, is the use of donor-derived bone marrow stem cells to treat the disease.

         

        Therapy Development for Epidermolysis Bullosa:

        Multiple new treatments are under development for epidermolysis bullosa (EB), a family of genetic disorders that lead to epidermal and mucosal fragility and blistering. Two recent studies in mouse models examined the efficacy of human recombinant type VII collagen (C7) for treatment of recessive dystrophic EB (RDEB), a severe form of EB caused by mutations in the C7 gene. In one study, recombinant C7 restored epidermal adherence when applied topically to wounds in RDEB mouse skin.1 In contrast, no C7 was detected when recombinant C7 was applied to intact RDEB skin, suggesting that topical application of C7 might be effective on existing wounds, but would not be useful for the prevention of new blisters. In the second study, recombinant C7 administered intravenously to RDEB mice migrated to unwounded RDEB skin and corrected the dermal-epidermal separation characteristic of RDEB, suggesting that intravenous administration of C7 might prevent new blisters and wounds.2 In addition to topical and systemic treatment with recombinant protein, researchers also are testing autologous blood and bone marrow transplantation for the treatment of RDEB. Early results suggest that transplanted donor cells home to wounds, secrete normal C7, and improve clinical outcomes for patients, and offer hope that a similar strategy could be used to treat patients with other inherited skin disorders.3 The NIAMS also is funding a Phase I clinical trial in which RDEB patients are being treated with grafts from their own skin that have been genetically engineered to express C7 (NCT01263379). Although they represent significant advances towards the goal of an effective therapy for EB, more work is needed to develop and test these treatments.

        References:

        1. Wang X, et al. Mol Ther. 2013. PMID: 23670575
        2. Woodley DT, et al. J Invest Dermatol. 2013. PMID: 23321924
        3. Toler and Wagner. The Lancet. 2013. PMID: 24095195

         

        Broad areas of potential research directions include:

        • Develop in vivo and ex vivo gene therapies, targeting single gene causal defects in skin diseases (e.g., various forms of epidermolysis bullosa).
        • Develop systemic therapies for inherited skin diseases, e.g., bone marrow transplantation and protein replacement therapy.
        • Investigate the use of small interfering RNAs to treat skin diseases through the modulation of expression of both normal and defective genes.
        • Investigate effective in vivo molecular and cell delivery strategies for healing of acute and chronic wounds.
        • Develop ex vivo and in vivo gene correction strategies for the treatment of genetic skin diseases.
        • Explore the therapeutic potential of various types of stem and progenitor cells, induced pluripotent stem (iPS) cells and embryonic stem cells, in the generation of artificial bioengineered skin replacements for acute and chronic wounds, and in the repair or regeneration of other tissues.
      2. Cutaneous and transcutaneous drug delivery

        Broad areas of potential research directions include:

        • Explore novel mechanisms of drug delivery into the epidermis and dermis.
        • Investigate topical delivery of small molecules as well as larger biomolecules, such as enzymes, monoclonal antibodies, and nucleic acids.
        • Develop transcutaneous drug delivery strategies for efficient and controlled administration of biological therapeutic agents for systemic diseases.
      3. Physical therapies

        Broad areas of potential research directions include:

        • Discover, develop and refine physical methods for skin diseases (diagnosis) and therapies.
    11. Skin Biology and Diseases: Clinical Research

      Skin diseases, which frequently create enormous quality-of-life issues, are not always seen as important research targets relative to illnesses with greater mortality and morbidity. However, the impact on patients' and families’ lives and their suffering are just as significant. Furthermore, some skin diseases are accompanied by systemic effects and co-morbidities.

      1. Clinical trials and outcomes measures
      2. The clinical trial is one of the most challenging steps between a basic discovery and its final application. A clinical trial should be based on solid pre-clinical studies, a clearly-defined patient cohort, an efficient recruitment infrastructure, a robust statistical design and unambiguous outcome measures. Combination therapies, evidence-based comparison of treatments, and cost-effectiveness are critical topics for future research.

        Broad areas of potential research directions include:

        • Develop clinical biomarkers that reliably predict disease progression and treatment outcomes and can be used as surrogate endpoints in clinical trials.
        • Create the resources required to move promising biomarkers from the bench to the clinic using state-of-the-art statistical, analytical, and computational methods.
        • Develop and validate new outcomes instruments that better measure disease severity and provide uniform descriptions and data that are comparable across studies.
        • Develop instruments that assess the impact of a disease on patient and family quality of life.
        • Develop methodologies for the collection of patient reported outcomes (PROs) and incorporate PROs in clinical studies/trials.
        • Explore alternative designs of clinical trials for rare skin diseases in which cohort sizes may be very small.
        • Conduct clinical trials in pediatric populations to determine safety, dosing, and efficacy of drugs approved for use in adults, with the ultimate goal of improving therapeutic options for children.
        • Establish novel disease outcome measures, as well as define novel signatures of onset and progression of autoimmunity and inflammation.
        • Explore alternative therapeutic applications of existing drugs for autoimmune and inflammatory conditions, comparing their mechanisms of action and efficacies with current therapies and long term safety follow-up.
        • Explore safety and efficacy of peptides and non-coding RNA based therapy.
      3. Epidemiology and health services research
      4. The incidence and morbidity of skin diseases are important subjects for epidemiological research. The distribution of health services for skin diseases is an example of the treatment of illnesses with low mortality, but significant physical and quality-of-life effects.

        Broad areas of potential research directions include:

        • Combine analysis of the natural history of disease with population-based epidemiological studies to determine disease prevalence.
        • Develop new measures to assess the burden of skin diseases on specific populations.
        • Facilitate observational and epidemiological studies of skin disease co-morbidities and gene-environment interactions that may trigger or exacerbate skin diseases.
        • Investigate skin disease co-morbidities as a potential contributor to health disparities.
        • Investigate whether therapeutic intervention(s) for a skin disease modifies the risk for developing co-morbidities.
        • Examine the cost-effectiveness and comparative effectiveness of therapies, and combination therapy approaches for skin disease treatment; develop the infrastructure needed to conduct these studies.
        • Research the effects of patient-health care system interactions in disease outcomes, with inclusion of minority and underserved populations.
      5. Prevention studies
      6. Broad areas of potential research directions include:

        • Develop strategies to identify, assess and reduce disease risk factors.
        • Conduct early intervention trials, to prevent onset or progression of disease.
        • Explore use of personal communication devices and the Internet as tools for education, monitoring and intervention.
    12. Skin Biology and Diseases: Behavioral and Biopsychosocial Research

      Environmental triggers of many skin diseases, such as ultraviolet radiation from the sun for skin cancer, are modifiable risk factors. These risk factors underscore the role of behavior as a contributor to disease, and create the opportunity for prevention and intervention through behavior modification. Patients with disfigurement from skin diseases are frequently affected by psychosocial problems due to social stigmas.

      Broad areas of potential research directions include:

      • Explore measures, including behavioral modification and protective strategies, to prevent skin exposure to ultraviolet radiation, which causes cancer and accelerated skin aging.
      • Conduct behavioral and psychobiology studies that have the potential to improve understanding of the mechanisms of skin disease.
      • Use social, commercial, economic and cognitive data (Big Data) to understand correlations between behavior and skin diseases.
      • Study the mechanisms by which stress affects skin disease progression and wound healing, and how stress management techniques and interventions impact disease outcomes and response to therapy.
      • Determine how the placebo effect influences disease outcome and response to therapy.
      • Investigate the management of chronic symptoms, such as itching and pain, as well as ways to minimize the effect of these symptoms on sleep and overall quality of life.
      • Use biopsychosocial approaches to understand how gender and/or ethnic and/or socioeconomic differences influence clinical disease outcomes, symptom perception and management, and interactions of patients with the health-care system.
      • Incorporate use of patient-reported outcomes instruments into clinical trials in skin diseases, to assess the effects of therapy on disease-specific quality of life.
  3. BONE BIOLOGY AND DISEASES

    The NIAMS bone biology and diseases programs cover a broad spectrum of basic, translational, and clinical research on the buildup and breakdown of bone. The acquisition and preservation of adequate bone mass, as well as the maintenance of the architectural and material qualities that confer strength on bones, are crucial for protection against fracture. Osteoporosis, or low bone mass, increases the risk of fracture with its attendant morbidity and reduced quality of life. Because osteoporosis is common among older people, particularly women past menopause, the prevention, diagnosis, and treatment of osteoporosis have major public health implications. Through its programs, the NIAMS supports studies of the regulation of bone remodeling; bone formation, bone resorption, and mineralization; as well as the effects of hormones, growth factors, and cytokines on bone cells. The Institute oversees several large epidemiologic cohorts that characterize the natural history of osteoporosis and identify genetic and environmental risk factors that contribute to fracture. The bone biology and diseases programs also support research on the causes, pathophysiology, and treatment of less common bone diseases, such as osteogenesis imperfecta and Paget's disease of bone, as well as on a wide range of developmental disorders of the skeleton, many of which are genetic in origin.

    1. Bone Biology and Diseases: Biology and Physiology of Bone

      1. Molecular and cellular mechanisms in bone

        The key processes in bone remodeling are the formation of new bone by cells called osteoblasts, and the breakdown, or resorption, of old or damaged bone by cells called osteoclasts. In a healthy adult skeleton, these processes are balanced by the overall process of bone remodeling. Osteocytes, fully mature osteoblasts embedded in mineralized bone, have emerged as a crucial population of cells for controlling bone physiology. There is also increasing interest in the function of lining cells on the surface of bone with regard to their characterization and role in normal physiology and pathologic states. An imbalance of resorption over formation results in bone loss, which can increase risk of fracture. Understanding the mechanisms that regulate the functions of osteoblasts, osteoclasts, and osteocytes, and hence influence bone resorption or bone formation, could yield new therapeutic targets. The ability to manipulate such mechanisms could also be essential for tissue engineering efforts using bone-forming cells.

        Broad areas of potential research directions include:

        1. Anabolic mechanisms: new bone formation by osteoblasts
          • Characterize the biochemical pathways that control the proliferation of osteoprogenitor cells.
          • Define the early and intermediate cell types in the differentiation of progenitors to mature bone-forming osteoblasts and osteocytes, and identify the factors that regulate progression through the cellular lineages.
          • Elucidate the mechanisms that control osteoblast activity and determine a cell's functional lifetime.
        2. Resorption of bone by osteoclasts, leading to bone loss
          • Characterize the biochemical pathways that control the differentiation of osteoclasts from progenitor cells in the monocyte/macrophage lineage.
          • Define the factors that regulate the maturation of progenitor cells into active multi-nucleated osteoclasts.
          • Elucidate the biochemical pathways that control osteoclast activity and functional lifetime.
        3. Mineralization of the bone matrix
          • Define the mechanisms that initiate and control the deposition of calcium phosphate crystals in the collagen matrix of bone.
          • Elucidate the factors that control the extent of mineralization in bone, and determine the effect of varying degrees of mineralization on the structural, functional and mechanical properties of bone.
          • Explore the causes of pathological calcification of soft tissues and explore measures that could prevent or reverse inappropriate mineralization.
        4. Cell-matrix interactions in bone
          • Characterize specific interactions between osteoblasts, osteoclasts, and components of the extracellular matrix of bone that influence cell differentiation or activity.
          • Determine interactions between osteocytes and the bone matrix to help explain processes underlying the embedding of the cells in mineralized matrix and the formation and maintenance of the osteocyte network.
          • Identify signaling pathways that are activated by cell-matrix interactions in bone.
        5. Cross-talk between different bone cell types
          • Define the molecules that are produced in one cell type and influence another, including those that may be transported in exosomes (e.g., micro-RNAs).
          • Elucidate sites where molecules that have effects on bone cells are produced.
          • Investigate the effects of signaling molecules originating in other cell types on target cells, including mechanisms mediating the coupling of bone formation with bone resorption.
          • Define the mechanisms that regulate osteocyte differentiation, including the formation of osteocyte dendritic processes and the lacunar-canalicular system.
        6. Mechanisms of fracture repair
          • Define the cell types and biochemical pathways involved in the recruitment of osteoprogenitor cells to fracture sites.
          • Elucidate the processes that lead to callus formation and remodeling of new bone, including the roles of loading, inflammation and vascularization.
          • Identify and characterize the factors leading to fracture non-unions (i.e., fractures that fail to heal).
        7. Response of bone to mechanical loading
          • Characterize the cell populations that mediate the anabolic response of bone to loading.
          • Define the role of the osteocyte network in mechanosensation and the response to loading.
          • Determine the resorptive response of bone to conditions of unloading, such as microgravity and disuse.
          • Elucidate the biochemical signals that are activated when bone cells are exposed to specific mechanical stimuli that may arise in bone under different loading conditions.
      2. Integrated physiology and pathophysiology of bone

        Over the past five years, the research community has made considerable progress in understanding connections between bone physiology and the broader network of biologic processes that involves many different organs and tissues. For example, muscle function and mass influence fracture risk, and energy metabolism (in which bone plays a role) affects muscle mass. In addition, interactions among conditions associated with aging, musculoskeletal function, and bone mass are still inadequately understood. Progress has been made in describing how diabetes, lipid metabolism and inflammation affect the musculoskeletal system, but a more integrated approach is needed.

        Scientists are now poised to make additional discoveries that will help to explain the connection between the skeleton and the nervous system, other mesenchymal tissues (e.g., fat, muscle, cartilage), the immune system, digestion and nutrition (including the role of the microbiome), and energy metabolism. Bone can be either a target or a regulator, and it likely performs both roles as it interacts with various systems in development, aging, and disease. Bone and the events responsible for bone health are connected with other biologic processes; many drugs for conditions apparently unrelated to bone may have unanticipated effects on the skeleton, and bone-building drugs may have unanticipated effects on other tissues within and outside of the musculoskeletal system (see box below).

        To fully appreciate interactions among organ systems, bone researchers will need to form interdisciplinary teams with scientists who specialize in other organ systems and metabolic pathways, and consider not only bone, but bone along with other organs and systems as an integrated unit.

         

        Anabolic Therapies and Strategies to Regenerate Bone and Other Musculoskeletal Tissues:

        The strategy of activating anabolic pathways in bone, cartilage, and muscle holds considerable potential to yield new therapeutic approaches for diseases relating to the musculoskeletal system as a whole or to its individual components. In bone, for example, recent research efforts have led to the identification of potential new treatment targets with powerful anabolic bone forming effects. These include the Wnt1 signaling antagonists sclerostin and DKK-1;2 agents that regulate or mimic PTH3 action (e.g., PTHrP,4 and calcilytic drugs aimed at the calcium sensing receptor); and components of the BMP/TGFβ5 pathways.

        Many of these targets and pathways are shared among different musculoskeletal tissues and play prominent roles in many other cells. Our understanding of the links between bone metabolism, energy metabolism, and the central nervous system is also improving. Recent advances have led to a recognition that, in order to fully explore the potential and consequences of anabolic therapies, bone, cartilage, and muscle must be viewed as components of a network that includes not only other tissues of the musculoskeletal system, but also other organs and systems.

        Taking a system-wide view would represent a paradigm shift, in that the bone, cartilage and muscle communities have traditionally focused on their single tissue of interest. More information about research needs and opportunities regarding anabolic therapies and strategies to regenerate the musculoskeletal system is at http://www.niams.nih.gov/News_and_Events/Meetings_and_Events/Roundtables/2013/anabolic_roundtable.asp.

          1 Wnt = wingless-type mouse mammary tumor virus (MMTV) integration site family
          2 dickkopf-related protein
          3 PTH = parathyroid hormone
          4 PTHrP = parathyroid hormone-related protein
          5 BMP = bone morphogenetic protein; TGFβ = transforming growth factor beta

         

        Broad areas of potential research directions include:

        1. Bone physiology and energy metabolism
          • Characterize the factors that determine whether mesenchymal progenitor cells differentiate into osteoblasts or adipocytes.
          • Determine the influence of body mass and body composition on bone homeostasis and bone strength. Such research could include studies to explain the relationship between bone physiology and the regulation of distinct fat depots (e.g., subcutaneous, visceral, and marrow fat).
          • Elucidate the relationship between bone physiology, obesity, and the regulation of glucose metabolism.
        2. Bone and the nervous system
          • Determine the influence of the nervous system on bone physiology, including the effects of central nervous system signaling and the influence of circadian rhythms.
          • Explore the roles of specific neurotransmitters and neuropeptides in bone.
        3. Bone and the hematopoietic and immune systems
          • Clarify the importance of interactions between bone cells and cells of the hematopoietic and immune systems, including factors in the bone marrow that influence bone physiology and bone remodeling.
          • Define the functions of regulatory molecules that may have roles in both bone physiology and the development and function of the immune system.
          • Examine the mechanisms underlying the destruction of bone in conditions of inflammation and autoimmunity.
        4. Bone and the vascular system
          • Determine the relationship between angiogenesis (the formation of new blood vessels) and the processes of bone growth and remodeling.
          • Explore possible parallels and interactions between bone mineralization and the vascular calcification that occurs in cardiovascular disease.
        5. Bone and cancer
          • Elucidate the mechanisms that underlie skeletal morbidity associated with malignancy, such as pathological bone destruction and formation.
          • Explore the nature of interactions between cancer cells and bone cells that mediate metastasis to bone.
        6. Bone as a component of joints
          • Characterize the interface and crosstalk between bone and cartilage in articular joints, including the possibility that signals originating in bone contribute to osteoarthritis.
          • Define the mechanisms that lead to pathological bone formation in joints, such as osteophytes (bone spurs) or spinal stenosis.
          • Elucidate the structure and function of interfaces between bone and ligaments and tendons.
        7. Bone and muscle
          • Describe molecular and cellular pathways of communication between bone and muscle, such as endocrine factors, neural influences, and exosomes.
          • Determine the roles of bone and muscle in the broad benefits of physical activity, including responses to mechanical stimuli and interaction with regulation of energy metabolism.
          • Explore possible synergies in therapeutic approaches that could yield improvements in both bone and muscle.
          • Identify differences and parallels in the healing of injuries to bone and muscle, including the origins of progenitor cells contributing to tissue regeneration.
      3. Genetics and genomics of bone mass and fracture risk

        Heredity influences many aspects of skeletal physiology, including the changes that occur with aging. Although genetic influences on the skeleton are complex, reflecting the contributions of many different genes, technological advances open the door to unprecedented understanding of individual risk for disease, and for personalized approaches to treatment. In recent years, high-throughput genotyping and sequencing technologies have been deployed in many clinical cohorts, largely substantiating the potential of genomic science to illuminate questions in skeletal biology and health. However, much of the heritability of skeletal traits such as bone mass and fracture risk remains unaccounted for. In addition, the causal variants underlying disease associations, as well as the actual biochemical processes influenced by those variants, remain unknown in most cases. Filling in these gaps will require an integrated analytical approach, incorporating multiple data types to reveal functional aspects of the genome in humans and animal models.

        Broad areas of potential research directions include:

        1. Functional genomics of skeletal tissues and cell types
          • Acquire and make broadly available, data reflecting the functional state of the genome (e.g., transcriptional activity, epigenetic characteristics) in cells of bone and cartilage.
          • Identify causal variants and molecular mechanisms accounting for genetic associations with skeletal traits.
          • Integrate insights from animal models, such as genetically modified mice and diverse inbred mouse strains, with human data to assign functional significance to specific gene variants.
        2. Translating genomic insights into improved skeletal health
          • Continue to define the genetic differences that underlie variation in bone formation, maintenance, and turnover.
          • Characterize the genetic influences that underlie ethnic and racial differences in bone mass, fracture risk, and fracture repair in humans.
          • Explore how environmental exposures and aging interact with genetics.
          • Identify genetic markers that predict response to drugs.
    2. Bone Biology and Diseases: Developmental Biology and Stem Cells

      1. Skeletal development

        The shaping and growth of bones during infancy and childhood are important for adult skeletal health. Research into the processes by which bones originate in the embryo and grow during skeletal maturation promises to illuminate causes and potential treatments of developmental disorders in humans. This knowledge may also lead to more effective methods for enhancing repair and regeneration of bone damaged by disease or trauma.

        Broad areas of potential research directions include:

        1. Early skeletal formation and growth
          • Elucidate the mechanisms that establish the location and shape of bones as they form during embryonic development.
          • Identify and explore mechanisms that control the cartilage-to-bone transition during endochondral ossification, including chondrocyte hypertrophy and apoptosis, mineralization, and the role of vascular ingrowth.
          • Explore environmental impacts on bone during both growth and development.
        2. Disorders of skeletal development
          • Define the causal factors underlying disorders of skeletal development, such as the osteochondrodysplasias. Such research would include the roles of specific genetic mutations.
          • Investigate the biological mechanisms that underlie the effects of mutations linked to disorders of skeletal development, as well as the cellular and molecular consequences of these genetic changes on developmental processes.
      2. Stem cells

        Bone cells differentiate from less specialized progenitor or stem cells, which can produce several different types of cells in response to various biochemical signals. Understanding these cells and the signals that guide them could improve tissue engineering and regenerative medicine approaches. Stem cells are also important targets of gene-based therapy strategies for genetic diseases of bone.

        Broad areas of potential research directions include:

        1. Mesenchymal progenitor cells
          • Define mesenchymal cell lineages to identify multi-potential precursors (adult stem cells) with osteogenic potential; explore whether the tissue from which these cells originate (e.g., marrow, adipose or periosteum) influences their differentiation potential.
          • Develop cell lineage markers to identify stages of osteogenic and chondrogenic differentiation.
          • Investigate the effects of regulatory factors, such as growth factors and bone morphogenetic proteins, on the proliferation and differentiation of progenitor cells.
        2. Embryonic and pluripotent stem cells
          • Examine the properties of animal and human embryonic stem cells with respect to osteogenic differentiation. Such research might include responses to specific growth factors and other regulatory molecules.
          • Explore the potential of iPS cells for differentiation along the osteogenic pathway. Studies could include investigating the differences between induced and embryonically derived stem cells and the effects of different strategies for inducing pluripotency.
    3. Bone Biology and Diseases: Imaging and Biomarkers of Bone Quality and Fracture Risk

      Simple assessments of bone mass or mineral content fail to take into account the large contributions of bone geometry, microarchitecture, and material properties that affect the ultimate mechanical performance of bone. Dual energy x-ray absorptiometry (DXA), the standard clinical measurement of bone density, is widely available and economical, but it gives only a rough estimate of bone quality and fracture risk. Understanding how architectural, material, and biochemical factors contribute to bone strength, and developing better methods of assessing these factors in the clinic, could lead to improved fracture risk prediction and monitoring of response to treatment.

      Broad areas of potential research directions include:

      1. Non-invasive measures of bone quality and fracture risk

        • Analyze the architectural and material factors that influence mechanical performance of bone by direct study of specimens and by modeling and engineering analyses.
        • Develop and validate non-invasive measures of bone quality (such as those based on magnetic resonance, computed tomography, and ultrasound), and algorithms that could improve the clinical assessment of fracture risk. Such measures would also provide early indications of the effectiveness of therapies.
        • Develop non-invasive tools that enable assessment of essential musculoskeletal functions, including biomechanical aspects of bone and muscle function.
      2. Outcome measures and surrogate markers

        • Identify biochemical markers of bone strength and fracture risk that can be measured in easily obtainable biomaterials such as serum or urine.
        • Investigate the utility of exosomes as bearers of tissue-specific biomarkers.
        • Test candidate biomarkers in well-characterized clinical cohorts for which bone mass, bone quality, and fracture risk can be assessed independently.
    4. Bone Biology and Diseases: Preclinical and Translational Research

      Interactions between laboratory and clinical researchers are essential for translating basic discoveries into new drugs, treatments, and diagnostics. They also foster environments in which clinical observations can prompt cellular and molecular studies that characterize a disease mechanism, leading to new biological insights as they advance the development of new therapeutic agents.

      Broad areas of potential research directions include:

      1. Pathobiological mechanisms

        • Characterize the molecular and cellular mechanisms underlying bone loss in common conditions such as sex hormone deficiency, vitamin D insufficiency, chronic inflammation, and steroid drug treatment.
        • Define the biological mechanisms underlying pathology in rare bone diseases, such as osteogenesis imperfecta and Paget’s disease of bone; apply knowledge of potential therapeutic targets to develop and test new interventions against rare bone diseases.
        • Investigate the mechanisms of increased bone loss and fracture risks due to diseases of other organs and systems (such as HIV infection and diabetes).
        • Examine biological processes that contribute to bone loss around orthopaedic implants and develop bone-preserving strategies for implant recipients.
        • Examine risk factors and mechanisms by which patients on bisphosphonates develop atypical femoral fractures.
        • Develop pre-clinical animal models that represent more accurately the initiation and progression of bone disease in humans.
      2. Therapeutic mechanisms

        • Define the biological mechanisms underlying the effects, including side effects such as atypical femoral fractures, of widely used medications, including drugs prescribed to prevent or reverse bone loss.
        • Examine why some therapeutic agents become less effective with long-term use.
        • Explore opportunities for discovery of newly identified molecular targets for new drug treatments.
        • Explore the use of multi-modality therapeutic approaches for the treatment of osteoporosis.
        • Determine the effects of drugs prescribed for diseases of other tissues and systems, since these drugs may have an impact on bone quality or fracture risk.
      3. Gene-based therapies

        • Develop methods for the recovery and re-introduction of cells in the marrow stromal/osteoblast lineage; explore the potential of embryonic and iPS cells as mediators of gene-based therapies.
        • Discover innovative ways to effect genetic modification of cells for the correction of genetic defects, or to manipulate gene expression for therapeutic purposes.
        • Establish methods for the inactivation of genes using strategies such as viral vectors, small interfering RNAs, and genome editing methods.
      Eliminating Disparities in Fragility Fracture Incidence and Outcomes among Racial and Ethnic Groups:

      People’s ethnicity and race, like their sex, influence the likelihood that they will develop osteoporosis and suffer fragility fractures of the hip, spine, and wrist. African ancestry is generally seen as protective against fracture, relative to European and Asian ancestry. However, the reality of disparities in bone health is more complex. Although the overall incidence of hip fractures decreased between 1995 and 2006 for men and women,1 additional work suggests that this decline is predominantly seen in whites.2

      Moreover, African American women are more likely than white women to die after hip fracture, and are less likely to be able to walk independently upon release from the hospital.3 This may be attributed largely to the fact that they tend to be older when they suffer a hip fracture. They also suffer from more comorbidities, which could lessen their ability to recover. The emerging biological links between bone, energy metabolism, and kidney function suggest that much can be learned from examining these interactions in populations where comorbidities such as diabetes, obesity, and chronic kidney disease are most prevalent. The connection between race and changes in bone density, quality, and fracture risk with time also suggests areas of molecular diversity that are ripe for exploration.4

      In addition to variations due to differences in genetic backgrounds, a range of environmental exposures, social and cultural issues, and access to and delivery of health care are likely involved. The changing demographics of the United States afford numerous opportunities for researchers to explore biologic and non-biologic causes of the well-documented disparities related to fragility fractures, and to test strategies to ensure that all Americans benefit equally from efforts to improve bone health.

      References:

      1. Brauer CA, et al. JAMA. 2009. PMID: 19826027
      2. Wright NC, et al. J Bone Miner Res. 2012. PMID: 22692958
      3. Cauley JA. Clin Orthop Relat Res. 2011. PMID: 21431462
      4. Chen Z, et al. J Bone Miner Res. 2011. PMID: 21590740

       

    5. Bone Biology and Diseases: Clinical Research

      1. Personalized medicine and clinical trials

        Characterization of disease mechanisms in the context of clinical studies may enable researchers and health-care providers to distinguish between disease subtypes that produce similar endpoints (e.g., fracture). Furthermore, improved understanding of individual genetic variation is expected to lead to improved prediction of who will respond best to different types of therapy. The NIAMS portfolio includes several studies that researchers could mine for information about variations in disease manifestations and patients’ responses to treatment. Research opportunities related to disparities in fracture risk and outcomes are described in the box above.

        In addition to examples identified under Imaging and Biomarkers, above, broad areas of potential research directions include:

        1. Clinical trials
          • Develop new therapies for prevention of fractures associated with osteoporosis and related conditions.
          • Assess the potential of combining therapeutic agents to achieve additive or synergistic treatment benefits.
          • Improve adherence to clinical protocols by developing and testing less burdensome dosing regimens or routes of administration and exploring approaches that reduce drug side effects.
          • Compare the effectiveness of different therapeutic approaches.
          • Develop and validate novel outcome measures and surrogate markers that can be used to improve clinical trial efficiency.
        2. Personalized medicine
          • Develop improved predictors of fracture risk that likely will reflect aspects of an individual’s environment, microbiomes, diet, lifestyle, and medical history.
          • Explore the co-morbidity of bone diseases with other health problems and examine possible interactions between bone-active drugs and medications prescribed for other conditions.
          • Examine variability in response to treatment and mechanisms for disparate responses (e.g., why some patients are refractory to certain treatments, and why some develop serious side effects).
          • Investigate the effects of genetic variation on response to treatments.
      2. Disease prevention and health promotion

        The NIAMS recognizes the importance of maintaining wellness in healthy populations and enhancing the well-being of those who experience bone disorders or diseases. Because motivating behavior change at a population level is an issue facing many NIH components, it may be possible to integrate research on bone health messages with other health promotion programs that include diet and exercise components. Social science approaches should be incorporated, where appropriate, into proposed research strategies.

        Broad areas of potential research directions include:

        1. Nutrition
          • Define the impact of nutritional status (e.g., vitamin D levels, protein intake) on bone health and fracture risk.
          • Develop and test strategies to promote bone health through improving nutritional status on a population level.
        2. Environmental and behavioral interventions
          • Develop and implement cost-effective strategies to promote healthy bone formation during infancy and childhood.
          • Examine the impact of physical activity levels on bone health and fracture risk; develop and test strategies to promote bone health through exercise and physical rehabilitation programs.
          • Explore the effects of environmental factors, such as smoking and environmental toxins, on skeletal health.
  4. MUSCULOSKELETAL BIOLOGY AND DISEASES

    The NIAMS musculoskeletal biology and diseases programs cover a broad spectrum of basic, translational, and clinical research centered on the interplay between the body’s muscles, bones, and connective tissues. These programs include research on the biology, structure, and function of joints and the surrounding tissues and applying this knowledge to a variety of diseases and conditions, including osteoarthritis (OA). Other programs addressed by this section cover tissue engineering and regenerative medicine to facilitate repair of damage caused by trauma to otherwise healthy tissue; imaging to improve the diagnosis and treatment of bone and joint disorders; and clinical research into the treatment and prevention of acute and chronic bone and joint injuries and orthopaedic conditions. Basic, translational, and clinical research interests related specifically to bone, muscle, or rheumatic diseases are addressed in their respective chapters within this plan.

    Many conditions addressed by the musculoskeletal biology and diseases programs are those that become more prevalent and problematic with age. Americans over 65 are the fastest growing segment of the U.S. population. This shift in the country’s demographics emphasizes the need for prevention and treatment strategies for diseases and conditions that affect joints and other musculoskeletal tissues. Investments in basic biology, combined with burgeoning opportunities in fields such as genetics/genomics and stem cells, will result in new opportunities for treatments and ultimately will improve clinical outcomes.

    1. Musculoskeletal Biology and Diseases: Biology, Structure, and Function

      1. Molecular and cellular biology of musculoskeletal tissues
      2. A complex series of biochemical pathways and cellular interactions underlie the physiology of healthy, damaged, and diseased musculoskeletal tissues. Understanding the process by which a multicellular organism develops from its early, immature form into a fully mature form may deepen knowledge of disease mechanisms, regeneration strategies, therapeutic targets, and treatment design. Likewise, understanding the behavior of mature cells in response to their own environment is critical for developing cell-based strategies to repair or regenerate musculoskeletal tissues. Insights into how biological, chemical, and mechanical conditions affect cell behavior, as well as that of the microenvironment and the tissues from which the cells originate, would facilitate progress in this area.

        Broad areas of potential research directions include:

        1. Development, maintenance, and degeneration
          • Characterize the molecules and signaling pathways that regulate the cellular activities (e.g., stem cell renewal, pluripotency, and differentiation) essential for development and maintenance of musculoskeletal tissues.
          • Elucidate the factors that control critical regulatory and signaling proteins specific to the development of tissues of the joint (e.g., articular cartilage, growth plate, meniscus, ligament, and tendon), and the development of tissue interfaces.
          • Elucidate the role of mechanical factors on cell signaling in the development of musculoskeletal tissues and in disease.
          • Investigate the role of specific cell populations (e.g., tendon and meniscus progenitor cells, synoviocytes) in tissue development and repair.
          • Describe how cells interact with their local and systemic environments to establish and maintain functional musculoskeletal tissues.
          • Examine the influences of various connective tissue components during normal joint maintenance and repair or during joint deterioration caused by disease.
          • Investigate whether biological activities leading to joint degeneration originate in the bone, interfacial tissues, ligaments, menisci, or synovia.

          i. Articular cartilage and chondrocyte biology

          • Characterize the interactions between cartilage matrix proteins and determine how mutations in individual cartilage matrix proteins affect chondrocyte behaviors and overall tissue structure and function.
          • Elucidate factors that contribute to chondrocyte cell death under normal or pathologic conditions.
          • Identify the features of the articular chondrocyte that distinguish it from other forms of cartilage.
          • Investigate the structure and function of the bone-cartilage interface.
          • Study the role of mechanical stimuli on the formation, maintenance, and destruction of extracellular matrices.

          ii. Tendons, ligaments, and menisci

          • Assess the effects of mechanical loading on the structural organization of menisci, tendons and ligaments.
          • Explore the structural organization and biogenesis of tendons, ligaments, and menisci, and their interfaces with muscle and bone.
          • Mechanisms underlying enthesis formation may be relevant to processes involved in joint degeneration.
          • Identify differences that contribute to improved healing of lateral meniscal damage or that inhibit repair of damage to the medial side.
          • Study mechanisms of tendinopathy to identify biomarkers and therapeutic targets.
        2. Genomics and epigenomics

          • Characterize the regulatory regions of genes relevant to musculoskeletal tissues.
          • Pursue in vivo studies such as quantitative trait loci (QTL) analyses to identify genes that define the properties of cartilage and joints.
          • Characterize epigenetic modifications that may relate to the development of healthy tissues and chronic diseases of the joint.
          • Explore the possible roles of epigenetic mechanisms in the differential onset and progression of musculoskeletal diseases.
          • Study the mechanisms by which gene mutations and epigenetic differences contribute to musculoskeletal diseases.
      3. Pathogenesis of osteoarthritis

        Osteoarthritis, the most common degenerative joint disease, affects not only the articular cartilage lining bone surfaces, but also components such as the subchondral bone, menisci, ligaments, capsule, synovial membrane, and periarticular muscles. Excessive, debilitating deterioration of joint tissues is a hallmark of osteoarthritis, regardless of whether it is caused by an inherited mutation, developmental or post-traumatic joint instability, failure of the neuromuscular system to protect against repetitive loading, or metabolic events that cause excessive joint remodeling. Studies of the cellular and biomechanical factors responsible for disease onset and progression or the promotion of healing and repair likely will require multidisciplinary research teams. Broad areas of potential research directions include:

        1. Influence of biomechanics and injury

          • Determine the biomechanical (including gait) and biochemical factors that influence initiation of the joint changes associated with early osteoarthritis, and the progression of these changes to severe, late stage osteoarthritis.
          • Evaluate biomechanical factors that influence joint deterioration after injury or during disease, or those that affect healing. Conduct research that may lead to potential therapeutic targets against damage to the ligaments, tendons, or menisci.
          • Map variations in gene expression during healing, remodeling, and adaptation to injury and disease (particularly tendinopathy), with particular emphasis on the cellular and molecular signals that link mechanical loading to gene expression.
          • Track and model post-injury changes in animal models to better understand the course of joint repair or deterioration.
          • Understand the basic biomechanical effects and related biochemical changes from obesity that lead to, or exacerbate, the development of osteoarthritis in children and adults.
        2. Inflammation

          • Further elucidate the mechanisms by which nutrients and inflammatory cytokines are transported among the extracellular matrix, synovial compartment, and bone marrow.
          • Define the relation between inflammatory cytokines and biological responses in joints and identify the signaling pathways that inflammation activates in the joint.
          • Identify and characterize inflammatory factors that act on subchondral bone and synovial tissue, as well as their roles in joint degeneration.
          • Distinguish between inflammatory pathways and factors that are involved after acute injury and during chronic disease.
          • Explore the contributions of obesity-associated genes to joint-damaging inflammation.
          • Study the role of pro-inflammatory molecules, including the advanced glycation end products that are associated with obesity and diabetes, in joint degradation.

          Research needs and opportunities related to inflammation’s role in osteoarthritis were discussed in greater detail at a 2013 NIAMS roundtable discussion.

        3. Pain

          • Assess the basic biological processes associated with spinal disorders, and their related pain syndromes. Study the genes and molecular pathways that give rise to painful osteoarthritic joints.
          • Study the pain pathways that are activated during the mechanical stresses that osteoarthritis places on joints. Much of our understanding of osteoarthritis pain is based on chemical induction of disease. However, pain due to physical joint degeneration (e.g., the mechanical action of bone rubbing on bone during severe osteoarthritis) could be caused by different mechanisms.
          • Determine why only some people with joint degeneration experience pain. Structural abnormalities are ubiquitous as people age, but pain is not.
        4. Genetic factors

          • Define the role of cellular aging and aging-associated epigenetic changes on the onset and progression of osteoarthritis.
          • Investigate the mechanisms of disease in genetically defined subsets of osteoarthritis.
          • Compare genetics of people who develop post-traumatic osteoarthritis shortly after injury and those who do not.
          • Investigate the early changes that occur in patients who go on to total joint replacement. One strategy would be to assemble cohorts with type II collagen defects. Advantages to studying this population include:
            • Pathogenesis and joint failure are more uniform and occur at an earlier age.
            • Patients are motivated to participate in research.
          • Assemble large, well-characterized collections of cases and matched controls with anterior cruciate ligament injuries to study development of post-traumatic osteoarthritis; where possible, adapt existing cohorts to genetic studies.
          • Determine the contribution of gene-gene and gene-environment interactions to the overall genetic influence on disease susceptibility.
          • Investigate the role of genetic influences on disease susceptibility, including genome-wide association strategies to detect multiple genes that contribute to a given phenotype.
          • Use genetically modified mice and new tools for genetic analysis in mice and humans to understand the genes involved in joint degeneration and to develop approaches for treating and preventing disease.
        5. Models for studying injuries and treatments

          The relevance of small animals, such as mice, to adult humans is less robust than many would like. More parallels are needed between small and large animal models. Some large animals (e.g., horses, certain breeds of dogs) are predisposed to develop musculoskeletal conditions. How do large animal models compare with small animal models that also are at risk of musculoskeletal disorders (e.g., guinea pig)? Is it possible to agree upon a single large animal model to parallel what has been done with the mouse?

          • Develop well-characterized, age-appropriate animal models for the study of osteoarthritis.
          • Develop and test models that more closely resemble how patients behave following an injury. Whereas many experiments are designed such that interventions are begun soon after injury, patients often wait before they are treated.
          • Study the local joint environment “post-injury” to identify approaches to protect tissues from damage and to promote tissue repair.
          • Examine long-term outcomes of anterior cruciate ligament repair in large animals. Current strategies for repairing torn anterior cruciate ligaments are of short-term benefit to patients.
    2. Musculoskeletal Biology and Diseases: Regenerative Medicine

      Regenerative medicine—tissue engineering and gene, cell, and pharmacological treatments that repair and restore tissue structure and function—is a multidisciplinary field involving both the life and physical sciences. Translational research and coordinated and collaborative research efforts play key roles in moving this field forward.

      1. Multidisciplinary research teams

        • Develop multidisciplinary research teams with expertise in the life and physical sciences (e.g., developmental biologists working with tissue engineers) and promote translational research.
        • Encourage cross-disciplinary discussions on broad issues in regenerative medicine and provide opportunities for cross-training and education for emerging scientists.
      2. Biological therapy development

        In addition to research topics identified under Molecular and cellular biology of musculoskeletal tissues, above, broad areas of potential research directions include:

        • Design and test methods to deliver molecular, cellular, or gene-based therapies for repairing musculoskeletal tissues, and for the treatment and prevention of osteoarthritis. Of particular interest are in vivo strategies to deliver cells, genes, or biomolecules.
        • Generate methods for site-specific, endogenous gene- and cell-modulation to facilitate integration of engineered tissues.
        • Accelerate the translation of cell-, gene-, and tissue engineering-based strategies into clinical testing by conducting studies in large animals.
        • Develop and test gene- or protein-based approaches for healing bone fractures, especially large bone defects.
        • Assess the use of progenitor cells as well as stem cells, such as iPS cells and embryonic stem cells, for musculoskeletal tissue applications.
        • Compare and standardize cell sources to identify promising approaches for advancing tissue engineering and regenerative medicine beyond the laboratory and into the clinic (e.g., adult stem cells from muscle, adipose tissue, or bone marrow vs. differentiated cells such as chondrocytes; adult stem cells vs. embryonic or iPS cells).
        • Develop strategies to recruit and direct endogenous progenitor or stem cells for regeneration.
        • Investigate the influence of stem and progenitor cells on inflammatory and immune responses and their effects on regeneration and healing.
        • Expand testing in preclinical models such as in large animal models for bench-to-bedside translation of regenerative medicine research. For example, the development of orthopaedic implants and surgical techniques, as well as the translation of the regeneration of weight-bearing musculoskeletal structures, all specifically require studying large animals.
      3. Scaffolds and biomaterials for tissue engineering

        Successful tissue engineering strategies require biomaterials and scaffolds that support the structural and functional development and maintenance of regenerated or repaired musculoskeletal tissues. Studying the biology of tissue development and organization often informs better biomaterial and scaffold designs. Such materials could be used when regenerating tissues in vitro for subsequent implantation in vivo, as well as in direct in vivo tissue regeneration and repair.

        In addition to research topics identified under Molecular and cellular biology of musculoskeletal tissues, broad areas of potential research directions include:

        1. Material development
          • Design biomaterials and scaffolds that direct the growth, differentiation, and organization of cells, by providing appropriate physical, chemical, and mechanical cues to form functional musculoskeletal tissues.
          • Explore innovative uses of the natural extracellular matrix as biomaterials or scaffolds to provide the structural and mechanical properties appropriate for functional musculoskeletal tissues, and develop biomaterials that mimic or result in functionally superior scaffolds.
          • Test biomaterials and scaffolds for their effects on the host immune system and inflammatory responses.
        2. Validation
          • Define functional outcome measures to evaluate tissue-engineered products.
          • Standardize and compare biomaterials and scaffolds to identify those with the most promise for advancing beyond the laboratory and into the clinic.
      4. Enabling technologies

        1. Methods and models
          • Develop and test minimally or non-invasive methods and devices to monitor engineered tissues, track cell fate, and deliver scaffolds in situ.
          • Develop methods to control responses and interactions between cells and their local environments.
          • Find new methods for sterilizing and preserving natural and synthetic materials and scaffolds so that they are suitable for implantation.
          • Facilitate the standardization of tissue culture reagents and protocols, safety procedures, outcome measures, testing and validation of animal models, and evaluation techniques.
          • Develop 3-dimensional in vitro human musculoskeletal tissue model systems to study human physiology and disease pathogenesis, as well as for drug discovery and toxicity studies, or for testing a proposed intervention’s feasibility, function, and safety in preparation for in vivo studies. Such research on the development of tissue-engineered, cell-based models would reduce the cost associated with animal models and lessen the scientific community’s need to study animals.
        2. Imaging for regenerative medicine
          • Develop real-time, minimally or non-invasive imaging modalities for in vivo monitoring of cell proliferation, differentiation, survival, migration, and integration.
          • Develop real-time, minimally or non-invasive imaging modalities to monitor tissue function repair, and integration processes in vivo.
          • Develop non-invasive imaging methods for measuring the functional capacity of tissue in small animal models, large animal models, and humans.
      5. Functional integration

        Research into the integration of regenerated or engineered tissues within a host organism must reflect the complex physiological interactions across multiple tissue types. Such systemic interactions include biological signaling processes, vascularization, innervation, and influences from the innate and adaptive immune systems. Preservation of structural and mechanical function, host and graft survival, and safety are also important.

        In addition to research topics identified under Enabling technologies, above, broad areas of potential research directions include:

        • Study the impact of inflammation and immune responses on regenerative processes.
        • Develop strategies to integrate engineered tissues with the host, while reducing adverse effects (e.g., immunogenicity, toxicity) and considering the ongoing disease process.
        • Validate and standardize functional outcome measures to determine success.
    3. Musculoskeletal Biology and Diseases: Preclinical and Translational Research into Joint Replacements

      Implants such as total hip and knee replacements have been shown to be effective tools to treat end-stage arthritis that has not responded to non-operative treatment, resulting in improved patient function and quality of life. If a joint implant fails, however, a patient may need a second surgery that is not likely to be as successful as the initial procedure. The main cause of failure is osteolysis (the disappearance of bone around an implant because of a reaction to microscopic particles from the implant). Numerous research opportunities exist to develop improved biomaterials, tools to better assess implant wear, and increased knowledge of the biology and pathophysiology of osteolysis. Moreover, biologic therapies and regenerative medicine approaches described above could serve as a bridge by delaying the age at which a person needs an implant. It would be valuable to have a technology that can allow someone who is young and active to reach an older age before needing a joint replacement.

      Broad areas of potential research directions include:

      1. Implant deterioration and failure

        • Analyze the biologic response to implant wear particles.
        • Characterize the features of wear debris that are most critical in determining the biological response to implant wear particles. Detailed mechanistic studies of the pathogenesis of periprosthetic osteolysis and implant loosening in different joints (e.g., hip, knee, spine) may be useful.
        • Determine the role of the innate and adaptive immune systems in the pathogenesis of implant failure.
        • Elucidate the effects of stress shielding on the bony structures (e.g., the acetabulum) that support implants.
        • Establish long-term wear behavior in the spine for conventional biomaterials in comparison with that in the hip and knee.
        • Explain and quantify the phenomena of third body wear (implant debris that becomes trapped between the two implant surfaces), and design preventive strategies to counter it.
        • Investigate the factors governing implant wear and the host tissue response to wear debris.
        • Pursue clinical and histopathological studies to better understand and diagnose metal hypersensitivity.
        • Understand the role of mechanical factors (e.g., motion and pressure) in the development of implant loosening.
        • Use genome-wide array analyses to understand the genetic risk factors for, and their relevance to, osteolysis.
      2. Improved materials

        • Explore the chemistry of interactions between biologic lubricants and implant-bearing surfaces.
        • Improve strength and fatigue resistance of polyethylene materials without compromising wear and oxidation resistance.
      3. Tools for testing

        • Develop methods to better assess the metal-on-metal wear of implants.
        • Measure wear in total knee and hip replacements. Automated image recognition software, for example, is one possible tool for such studies.
        • Standardize mechanical testing strategies to assess fracture resistance of new polyethylene formulations.
        • Study the efficacy of computed tomography (CT) and MRI scanning in assessing the extent of implant osteolysis.
    4. Musculoskeletal Biology and Diseases: Biochemical and Imaging Biomarkers

      Many musculoskeletal diseases are chronic and have long, variable clinical courses. These conditions take decades to develop and can be difficult to characterize. Biomarkers of disease and responses to treatment are often assessed by measuring biochemical factors in blood or body fluids, or through analyses of genetic biomarkers from tissues or peripheral blood cells. Broad, innovative use of imaging techniques, in combination with measurements of biochemical markers, also could allow the early identification of disease onset, predict disease progression, and enable the direct monitoring of responses to tissue repair and therapeutic interventions. For many musculoskeletal conditions, responses to therapies are difficult to determine. Researchers are beginning to believe that, as with many disorders, a battery of biomarkers may be more useful than a single biomarker.

      The box below describes an NIH effort to create a public resource to validate imaging and biochemical biomarkers for osteoarthritis.

      Osteoarthritis Initiative (OAI):

      A limited number of therapies exist for osteoarthritis (OA) treatment. Most only relieve pain and reduce disability; none slows or halts disease progression. One barrier to the development of drugs that block the underlying causes of OA symptoms is the lack of objective and measurable standards for disease progression by which new drugs can be evaluated. To overcome this problem, the NIH—with input from the U.S. Food and Drug Administration—partnered with private sponsors to create the Osteoarthritis Initiative (OAI). When complete, the OAI will provide an unparalleled state-of-the-art database showing both the natural progression of the disease and information on risk factors, joint changes, and outcome measures. All data are freely available to researchers worldwide, who can develop hypotheses about possible OA biomarkers of disease onset and progression, test their theories, describe the natural history of OA, and investigate factors that influence disease development and severity. Scientists also can use the OAI to identify potential disease targets and to develop tools for measuring clinically meaningful improvements.

      By the end of FY 2014, investigators will have collected survey, clinical, and image data and biological samples from approximately 4,800 people at baseline, 12-, 24-, 36-, 48-, 60-, 72-, 84-, and 96-month time points.

      For further information, see the OAI page on the NIAMS website.

       

      In addition to the opportunities regarding biomarkers and imaging methods described under Preclinical and Translational Research into Joint Replacements, above, broad areas of potential research directions include:

      1. Identification, qualification, and validation

        • Broaden biomarker investigations to include genetic markers of disease or markers that may predispose individuals to a heightened risk of disease progression, worsening, and severity, or those biomarkers that predict responses to treatments.
        • Conduct basic exploratory studies to identify lead candidate biomarkers.
        • Develop and apply new technologies for the discovery of biomarkers of disease onset, progression, and response to therapy.
        • Identify post-injury joint changes that cause or predict osteoarthritis.
        • Identify biomarkers that will be useful for predicting overall outcomes or those in specific subsets of patients. Of particular interest is the use of existing repositories and databases to qualify and validate the biochemical and structural changes associated with onset and progression of osteoarthritis.
        • Combine markers of cartilage and bone catabolic activity, imaging markers, proinflammatory cytokines, and gait analysis data to gain insights into the optimal timing of joint replacement in the disease process, and the identification of patients who are at risk of implant failure.
        • Study non-invasive biomarkers to facilitate early diagnosis and to monitor treatment of musculoskeletal infections, including those around implanted devices.
      2. Resource development and application

        • Apply existing and newly developed imaging technologies when studying disease and identifying possible imaging biomarkers associated with disease onset and progression.
        • Create and standardize multiplex arrays that simultaneously measure multiple biomarker candidates in a single sample.
        • Develop imaging technologies and systems biology approaches and apply them to the discovery of biomarkers of disease onset, progression, and response to therapy.
        • Produce and assemble resources to assist investigators engaged in biomarker development and validation.
        • Standardize imaging methods across sites so data can be shared and compared.
        • Develop image registration methods that can be used in longitudinal studies.
        • Standardize methods for evaluating changes in human joint structure—synovium, cartilage, bone, ligaments, tendons, and meniscus—associated with normal aging. Differentiate these changes from those associated with symptomatic joint diseases like osteoarthritis.
        • Use existing infrastructure, such as databases and clinical cohorts, to move promising biomarkers from the laboratory to the clinic through the application of state-of-the-art statistical, analytical, and computational methods.
    5. Musculoskeletal Biology and Diseases: Clinical Research

      Characterization of disease in the context of clinical studies may enable researchers and health care providers to distinguish between disease subtypes that produce similar endpoints (e.g., osteoarthritis, connective tissue injuries). The NIAMS portfolio includes a number of large clinical trials and cohort studies (e.g., the Osteoarthritis Initiative, see box above) that researchers could mine for information about variations in risk factors, disease manifestations and patients’ outcomes.

      As investigators consider clinical studies of musculoskeletal and orthopaedic conditions related to the broad areas described below, they are encouraged to consider the following issues:

      • The role of personalized medicine in maintaining or restoring musculoskeletal health.
      • Use of registries, electronic medical records and large databases to perform clinical studies.
      • The feasibility of using a central institutional review boards for multi-site clinical projects.
      • Integration of social media and technology into clinical studies to make research more efficient (i.e., more powerful and less expensive).
      1. Behavioral and psychosocial research

        Behavioral and psychosocial factors are involved in the onset, course, and outcome of chronic diseases. These factors are central in the experience of symptoms (such as pain and fatigue), disease-related distress, and coping with chronic disease, disability, and, to varying extents, the success of prevention and treatment approaches. Interdisciplinary research that integrates behavioral and biomedical sciences is likely to result in enhanced management of these diseases and reduced disability, and may shed light on the complex mechanisms involved in disease processes.

        Research needs and opportunities were discussed in 2010 at a roundtable on Psychosocial and Behavioral Therapies for Musculoskeletal and Rheumatic Disease Outcomes. Broad areas of potential research directions include:

        • Assess the willingness of members of racial and ethnic sub-populations of the United States to undergo total joint replacement and develop strategies to ensure that all Americans who have severe osteoarthritis can make the best possible decisions regarding their treatment.
        • Determine the mechanisms and outcomes of behavioral therapies for treating chronic musculoskeletal conditions and injuries.
        • Develop and validate more accurate and appropriate outcome measures for the study of disability related to musculoskeletal conditions and injuries.
        • Clarify the impact that psychological distress has on recovery after musculoskeletal trauma, and design strategies to prevent or reduce it.
        • Determine which outcomes of musculoskeletal diseases and procedures are influenced by modifiable attributes such as beliefs, attitudes, and psychological states and pursue strategies that will lead to better health states.
        • Determine which behavioral interventions can be delivered by someone other than a physician without losing their effectiveness.
        • Explore strategies for sustaining behavioral interventions that are known to be effective (e.g., weight loss).
      2. Childhood musculoskeletal conditions

        The cost of childhood musculoskeletal conditions is enormous. Although some conditions can be treated with a full restoration to active life, others can result in early death or progressive problems into adulthood. Still others present lifelong challenges to the affected individual, his or her family, and society.

        Prevention of childhood injury is addressed under Fractures and Musculoskeletal Trauma, below. Other broad areas of potential research directions include:

        • Develop physiologic interventions to correct skeletal deformities and neuromuscular disorders, including the muscular dystrophies.
        • Study the musculoskeletal implications and complications of rheumatic diseases in children. Examples include growth delay, osteoporosis, and avascular necrosis.
      3. Osteoarthritis

        Osteoarthritis is by far the most common type of arthritis, and the percentage of people who have it grows higher with age. Although osteoarthritis affects an estimated 27 million Americans age 25 and older, very few, if any, disease-modifying agents exist.

        Broad areas of potential research directions include:

        1. Risk factors
          • Define and stratify risk factors for osteoarthritis development in individuals and populations. These include body weight, previous joint injury, family history, diet, physical activity, coincident pathology of other tissues and organs, and medication use.
          • Determine the effects of changes in modifiable risk factors on the onset and progression of osteoarthritis.
          • Develop or modify strategies, including preventive and rehabilitative approaches, to reduce the development of disability and functional limitation associated with the onset and progression of osteoarthritis.
        2. Treatments (also see Joint replacement, below, and Behavioral and psychosocial research, above)
          • Explore rehabilitation and physical therapy strategies to reduce risk for impairment from osteoarthritis progression.
          • Identify and characterize agents and approaches to decrease the disability and pain related to tissue degeneration in osteoarthritis.
          • Investigate strategies to prevent or reverse structural modifications of diseased joints; identify new targets and develop corresponding therapeutic agents.
          • Pursue innovative treatments (such as biologics) to slow or prevent joint degeneration.
      4. Joint replacement

        As described under Preclinical and Translational Research into Joint Replacements, above, implants for total hip and knee replacements are effective treatments for people who have end-stage arthritis. Although infection at the site of a total joint replacement is rare, it can be devastating and require lengthy hospitalization. Other complications include implant loosening or failure, which require additional surgeries that are less likely to be as successful as the initial joint replacement. In addition to preclinical research examples noted under Preclinical and Translational Research into Joint Replacements and Biochemical and Imaging Markers, above, broad areas of potential patient-oriented research directions include:

        1. Outcomes
          • Analyze outcomes of revision total knee and hip replacements. Such studies could be useful for identifying grafting techniques that lead to well-fixed implants, defining the roles of bone and synthetic graft materials, and quantifying graft incorporation and bone resorption.
          • Develop and implement strategies to prevent implant-related musculoskeletal infections.
          • Investigate the effects of anabolic agents post-operatively to see whether they can significantly increase osteointegration of the implant and decrease subsequent loosening.
          • Test the long-term biocompatibility and wear properties of alternative bearing surfaces.
          • Standardize the criteria for determining the therapeutic effects of non-surgical interventions (such as drugs or rehabilitation strategies) to prevent or treat implant osteolysis, to enable comparison of interventions across different studies.
        2. Techniques and timing
          • Assess the impact of small incision, minimally invasive surgical approaches, and robotic surgery on functional outcomes, complications, and revision rates.
          • Develop and validate pre- and post-operative rehabilitation strategies, especially for hip and knee replacement.
          • Study the clinical and economic impact of diagnosing implant osteolysis earlier.
      5. Spinal disorders

        Many spinal disorders are common, costly, and potentially disabling. Low back pain affects millions of people around the world and has an enormous socioeconomic impact. A frequent cause of disability, low back pain causes employees to lose many days of work each year. Although low back pain constitutes an important public health issue, little is known about its causes. A considerable investment in a study of surgical and non-surgical therapies for common causes of low back pain has yielded important results (see box below). However, much remains to be discovered about strategies to improve the lives of those who are affected by back pain or related disorders. To facilitate chronic low back pain research, an NIH task force developed research standards that include defining the problem of cLBP, assessing its impact on patients' lives, identifying the minimum dataset that should be collected in cLBP research, and defining the best outcomes to evaluate treatment effectiveness.

        The Spine Patient Outcomes Research Trial (SPORT) for Low Back Pain:

        World-wide, low back pain is the leading cause of disability, as measured by years lived with disability (YLDs), and the sixth greatest source of disease burden as measured in disability-adjusted life years (DALYs).1 The Spine Patient Outcomes Research Trial (SPORT) for Low Back Pain is collecting data to help patients and their health care providers determine the most appropriate treatment for this common, disabling condition.

        Before SPORT, many people who had chronic low back pain were conflicted about whether to undergo surgery. Some were not sure surgery was worth the risk, while others feared that delaying surgery might cause even more damage. SPORT has demonstrated that, indeed, surgery is better than nonoperative treatments for the three most common causes of severe low back pain: intervertebral disc herniation and lumbar spinal stenosis with or without degenerative spondylolisthesis (the slipping of vertebrae). However, people who have one of these conditions are not subjecting themselves to further harm if they adopt a "wait-and-see" approach before committing to surgery.

        The benefits of surgery to correct spinal stenosis, for example, were apparent as early as six weeks after surgery.2,3 Those patients who had severe slippage and discomfort due to lumbar spinal stenosis with degenerative spondylolisthesis seemed to benefit the most.4 Although people who did not have surgery reported some improvement two years into the study, those who had surgery seemed to be doing considerably better.2,3 Additionally, SPORT showed that combining two surgical procedures—decompressive laminectomy and fusion—did not help patients who had lumbar spinal stenosis without degenerative spondylolisthesis any more than decompressive laminectomy alone.5 The findings regarding intervertebral disc herniation were equally meaningful. Two and four years after surgery, patients who had surgery for a herniated upper lumbar disc felt significantly better than those who had had a lower disc repaired.6,7 Although more costly than approaches such as medications and physical therapy, lumbar diskectomy is a cost-effective treatment.7

        These benefits with surgery were seen for all conditions at four years,8,9,10 and for disc herniation at eight years.11 Eight-year results for the other two conditions are pending. Of note, those patients with disc herniation who continued to participate in SPORT eight years after joining the study reported consistent results between their four- and eight-year surveys, regardless of whether they had surgery or not.11

        References:

        1 Hoy D, et al. Ann Rheum Dis. 2014. PMID: 24665116
        2 Weinstein JN, et al. N Engl J Med. 2007. PMID: 17538085
        3 Weinstein JN, et al. N Engl J Med. 2008. PMID: 18287602
        4 Pearson AM, et al. Spine. 2008. PMID: 19050582
        5 Tosteson AN, et al. Ann Intern Med. 2008. PMID: 19075203
        6 Lurie JD, et al. J Bone Joint Surg Am. 2008. PMID: 18762639
        7 Weinstein JN, et al. Spine. 2008. PMID: 19018250
        8 Tosteson AN, et al. Spine. 2008. PMID: 18777603
        9 Weinstein JN, et al, JBJS. 2009. PMID: 19487505
        10 Weinstein JN, et al. Spine. 2010. PMID: 20453723
        11 Weinstein JN, et al. Spine. 2014. PMID: 24153171

         

        Broad areas of potential research directions include:

        • Develop and evaluate new treatment methods and technologies for degenerative disc disease, including the use of an artificial disc and nucleus, and the use of regenerative medicine techniques to reverse the process of disc degeneration.
        • Pursue clinical studies to address the management of spinal disorders that are common and costly, and for which consensus regarding preferred treatment is lacking.
        • Study the efficacy and effectiveness of emerging technologies in treating spinal disorders.
      6. Fractures and other types of musculoskeletal trauma

        In addition to the health-care expenditures associated with treatment, fractures and other types of musculoskeletal trauma cost billions of dollars in terms of lost employment. Traumatic musculoskeletal injuries can lead to lifelong disability. Trauma is the leading cause of death after the first year of life; it exceeds all other causes of childhood death combined. Treatment of patients who suffer fractures in conjunction with trauma to other organ systems (e.g., traumatic brain injury) is a challenge in musculoskeletal care. After injury prevention, methods to reduce complications, disability, and mortality are paramount. Further refinement of operative and non-operative techniques and rehabilitation after fractures or skeletal trauma will improve patient outcomes, enhance the lives of patients and their caregivers, and facilitate their return to the workforce.

        In addition to the relevant Behavioral and psychosocial research opportunities, above, broad areas of potential research directions include:

        1. Prevention
          • Elucidate the mechanical forces that contribute to or cause joint injuries (e.g., ACL tears, herniated discs) and understand the consequences of cumulative trauma disorders of soft tissues. Such studies could be useful for preventing injuries and developing protective devices for preventing these injuries.
          • Explain the role personalized medicine can play in maintaining bone and joint health.
          • Preventing childhood/adolescent injuries.
        2. Management
          • Further establish the outcomes and cost-effectiveness of treatments for specific fractures and other musculoskeletal injuries.

          i. Fractures

          • Develop and validate measures that better assess fracture healing.
          • Test methods to diagnose and treat injuries to and around growth plates, to prevent growth disturbances.
          • Improve strategies for repairing fractures in older people.

          ii. Damage to cartilage, connective tissue, and fibrocartilaginous tissues (including menisci)

          • Study the outcomes of treatments of joint injuries to prevent post-traumatic osteoarthritis.
          • Optimize methods of repairing or replacing damaged menisci that are causing pain or dysfunction.
          • Improve strategies to diagnose and treat symptomatic rotator cuff tears.
          • Explore the natural history of rotator cuff tears to understand why some are more symptomatic than others.

          iii. Trauma to multiple organ systems

          • Enhance strategies to recognize and treat combined injuries, especially as they relate to the timing and type of surgery in multiple trauma patients (e.g., those suffering fractures in addition to head injury, chest and/or abdominal injury, or shock).Improve surgical strategies for correcting injuries affecting multiple systems, such as compartment syndromes and mangled extremities.
        3. Study design
          • Implement strategies to standardize clinical studies of interventions that influence fracture and soft tissue healing, using both objective and subjective parameters.
      7. Sports and fitness

      8. Fitness is associated with good health and a sense of well-being. Numerous studies have shown the beneficial effects of exercise in disease prevention, yet one of the problematic effects of exercise is injury. Musculoskeletal soft tissues are vulnerable to injury and damage as the result of overuse and/or trauma. These injuries are often life-altering. In addition, the cartilage loss that leads to joint degeneration is generally slow and progressive with age.

        In addition to examples noted under Osteoarthritis and Fractures and other types of musculoskeletal trauma, above, broad areas of potential research directions include:

        1. Physical activity requirements
          • Better understand how particular fitness requirements vary with sex, age, and conditions that limit mobility. Such knowledge is important for efforts to encourage physical fitness and promote health.
          • Identify markers of bone, cartilage, and muscle quality that could facilitate studies into which types of exercise are best to promote musculoskeletal health.
        2. Injury prevention
          • Characterize sex differences in ultra-high performance sports as the groundwork for focused programs to prevent injuries and overuse disorders commonly seen in these athletes.
        3. Treatment and rehabilitation
          • Apply physical medicine and rehabilitative strategies to soft-tissue injuries, to restore maximal function.
          • Determine the type and level of exercise that is effective for minimizing the progression of specific diseases and promoting restoration of musculoskeletal function. Such knowledge could translate into "exercise prescriptions."
  5. MUSCLE BIOLOGY AND DISEASES

    The NIAMS muscle biology and diseases programs encourage basic, translational, and clinical research on the biology and disorders of skeletal muscle. Studies address questions about muscle developmental biology, growth, maintenance and hypertrophy; the physiology of muscle contraction; the structural biology of the contractile apparatus; mechanisms of muscle diseases and disorders; biomarkers and outcome measures for clinical and preclinical studies; and natural histories of muscle conditions. These programs also support the development and testing of therapies for muscle diseases and disorders, including cell and gene therapies, and small molecule drugs and biological products, exercise and other physical interventions. In addition to research projects, NIAMS supports training and career development, scientific conferences and research infrastructure, such as core facilities that enhance and accelerate research sponsored by the NIH and other public and private organizations.

    The muscular dystrophies are an area of emphasis for the NIAMS muscle programs. NIAMS participates in the Muscular Dystrophy Coordinating Committee (MDCC), which includes stakeholders from Federal and private organizations. Research objectives for the muscular dystrophies will be presented in this NIAMS Long-Range Plan where they overlap with objectives for other muscle diseases. A more specific and detailed description of the research objectives for the muscular dystrophies is found in the MDCC’s Action Plan for the Muscular Dystrophies (see box below). The plan—which the MDCC is updating with input from experts in the fields of muscular dystrophy pathophysiology, diagnosis, treatment, and patient and family care—will be available in FY 2015 at http://www.ninds.nih.gov/about_ninds/groups/mdcc/.

    Action Plan for the Muscular Dystrophies:

    As the lead agency of the Muscular Dystrophy Coordinating Committee (MDCC), NIH is coordinating the revision of the MDCC Action Plan for the Muscular Dystrophies. As with the 2005 plan, the 2015 document (which will be available at http://www.ninds.nih.gov/about_ninds/groups/mdcc/) will reflect scientific opportunities in:

    • Disease mechanisms,
    • Diagnosis and screening,
    • Preclinical therapy development,
    • Clinical development, and
    • Living with muscular dystrophy.

    Priorities will reflect the expertise and judgment of leading basic and clinical researchers, physicians, and patient advocates who are devoted to the field of muscular dystrophy.

     

    1. Muscle Biology and Diseases: Skeletal Muscle Biology

      1. Cell and Developmental Biology

        Understanding healthy and diseased muscle states requires basic research on skeletal muscle tissue development and maintenance. Studies of the pathways controlling muscle formation, for example, are likely to have implications both for diseases characterized by muscle deterioration, and for the regeneration of muscle after injury.

        Understanding the natural repair processes after injury or while recovering from disease could lay the foundation for improved therapies. More details about opportunities that could be facilitated by basic studies of muscle’s anabolic processes are described at http://www.niams.nih.gov/News_and_Events/Meetings_and_Events/Roundtables/2013/anabolic_roundtable.asp.

        Broad areas of potential research directions include:

        1. Development

          • Define the factors that influence embryonic cell fate and those that control cell proliferation, migration, and differentiation in myogenesis.
          • Elucidate the mechanisms underlying myogenic chemotaxis, adhesion, and fusion.
          • Determine when individual myonuclei are incorporated into muscle tissue during development and their progenitor cell sources.
          • Identify and characterize elements that dictate tissue patterning (e.g., muscle size, shape, fiber composition) during development.
          • Study the formation of the contractile apparatus, myotendinous junctions, and other complex structures comprising mature muscle.
          • Understand how muscle fibers integrate with other tissues (e.g., adipose tissue, immune cells, tendons) during development.
        2. Growth and maintenance

          • Characterize the cell types that contribute to muscle growth and maintenance. Studies on the activation, migration, proliferation, and differentiation of muscle stem cells, including satellite cells and other progenitors, during cell or tissue turnover and repair are of interest.
          • Explore satellite cell heterogeneity. Individual fibers or muscles may have specific subpopulations of satellite cells, and there may be differences between species.
          • Determine when individual myonuclei are incorporated into muscle tissue during hypertrophy and their progenitor cell sources.
          • Examine the functional and gene expression differences among muscle fibers or myonuclei and uncover the differences (e.g., in gene expression patterns) responsible for muscle specialization.
          • Define the factors that regulate gene and protein expression controlling muscle growth, fiber type determination, and hypertrophy (e.g., epigenetic changes, microRNAs).
          • Identify and characterize modulators of signaling pathways that increase muscle fiber growth and cell proliferation (e.g., myostatin inhibitors, IGF1 signaling agonists).
          • Define genetic variations that enhance or limit the normal anabolic responses of skeletal muscle to resistance or endurance training, or that protect from or exacerbate atrophy or cachexia.
          • Investigate the tissue, cellular, and subcellular responses to environmental factors including exercise, disuse, or nutrition.
          • Explore the molecular and biochemical changes that are responsible for differences in muscle mass, susceptibility to atrophy, and response to exercise that are seen in men and women, in people at different ages, or in people from different racial backgrounds.
          • Study the catabolic processes of autophagy and proteolysis as they relate to turnover of muscle fiber components.
      2. Cell Physiology and Biophysics

        Studies of normal muscle cell physiology are likely to uncover new pathways and processes that researchers could use to develop treatments against muscle diseases.

        Broad areas of potential research directions include:

        1. Excitation/contraction coupling
          • Determine the structures and functions of the components of the sarcolemma and sarcoplasmic reticulum required for muscle cell excitation and intracellular calcium handling. Studies of how the membranes communicate are also of interest.
          • Define calcium’s role in contraction and explore strategies to restore muscle function by correcting intracellular, compartmental, and extracellular calcium concentrations and sequestration. Ions beyond calcium are also of interest.
        2. Structural biology and biophysics
          • Elucidate the structure and function of macromolecular complexes essential for skeletal muscle function and maintenance, including the dystrophin/glycoprotein complex, contractile apparatus, and ion channel complexes.
          • Better characterize the assembly of protein complexes, including the roles of chaperones.
        3. Cellular biomechanics
          • Determine the mechanisms by which mechanical stimuli influence muscle assembly and turnover.
          • Determine the relationships of muscle protein synthesis and force production during hypertrophy and atrophy.
          • Better characterize how the contractile apparatus and links to the extracellular matrix are modulated during fiber repair and regeneration.
          • Investigate how muscle strain injuries affect the components and organization of macromolecular complexes.
        4. Mitochondrial biogenesis, turnover, and function
          • Better understand the regulation of muscle mitochondrial function and turnover in normal and disease states.
          • Understand the effects of exercise on mitochondrial biogenesis.
          • Better understand muscle mitochondrial function and uncoupling in energy metabolism.
      3. Integrated Physiology and Metabolism
      4. Studying muscle as a system that interacts with other tissues and organs will provide insights into the weakness and fatigue that occur with numerous non-muscle diseases. This research will also explain how physical activity contributes to overall health and well-being, beyond simply improving muscle strength and cardiovascular fitness. These emerging areas of research have garnered considerable attention in recent years and were the topics of two NIAMS-sponsored roundtables (see boxes below). Both meetings emphasized that characterizing the mechanisms responsible for the connections between muscle and other organ systems will likely entail collaborations among researchers from multiple disciplines.

        Mechanisms of Exercise-Induced Health:
        Moderate to vigorous activity benefits the human body in a multifactorial manner. Although exercise is associated with lower rates of obesity, even obese individuals can enjoy the positive effects of physical activity independent of its effect on weight. Biological changes associated with better health include a less atherogenic lipid profile, greater insulin sensitivity, lower arterial stiffness and blood pressure, better endothelial function, higher bone density, muscular strength and endurance, and aerobic fitness. Improved mental health (e.g., less anxiety, less depression, a more positive self-concept) is an additional, well-documented result.

        Provocative scientific research that addresses the cellular changes that contribute to these improvements is beginning to emerge.1,2 Additional work leading to a more complete understanding of the mechanisms linking regular exercise to disease prevention and improved health could contribute to decreased burden of common diseases and a significant increase in quality-adjusted life years for many people. An understanding of the processes connecting exercise and disease prevention/amelioration may also contribute to the efficacy of physical activity as a treatment for multiple health conditions.

        More information about research needs and opportunities regarding the molecular and cellular mechanisms by which exercise contributes to health is at http://www.niams.nih.gov/News_and_Events/Meetings_and_Events/Roundtables/2010/exercise_roundtable.asp

        1 Owusu-Ansah E, et al. Cell. 2013. PMID: 24243023
        2 Lira VA, et al. FASEB J. 2013. PMID: 23825228

         

        Impact of Muscle Physiology Research on Common Diseases and Disorders:

        Diseases and conditions such as musculoskeletal atrophy due to disuse, age-associated sarcopenia, cachexia (as seen with chronic heart failure, sepsis, severe burns, cancer, HIV/AIDS, and other disorders), debilitating muscle fatigue, and heat illness all involve perturbations to normal skeletal muscle physiology. While support of clinical trials and population studies in these areas commonly falls under other NIH components’ missions, NIAMS remains interested in understanding the mechanisms by which these conditions affect muscle physiology.

        More information about how muscle research could inform the prevention and treatment of common diseases and disorders, and examples of how studies of these diseases could inform our understanding of muscle physiology, is at http://www.niams.nih.gov/News_and_Events/Meetings_and_Events/Roundtables/2011/musc_phys_roundtable.asp.

         

        Broad areas of potential research directions include:

        1. Muscle as an endocrine organ and metabolic tissue
          • Define the metabolic and hormonal interactions among muscle, bone, and fat during normal, exercise, and disease states.
          • Examine muscle’s role as a heat-producing organ in the regulation of core temperature.
          • Explore the effects of temperature on muscle function.
          • Identify and characterize factors released into circulation during skeletal muscle activity that impact other tissue and organ systems.
          • Investigate compounds that improve muscle’s ability to metabolize energy sources.
          • Understand the regulation of muscle protein synthesis and degradation, as muscle serves as a source of amino acids available to other tissues in healthy and disease states.
        2. Immune and inflammatory responses
          • Characterize the positive and negative effects of inflammation on regeneration after exercise, injury, or disease. Better understand the interaction of muscle cells with lymphocytes and macrophages.
          • Determine the mechanisms by which exercise alters immune responses and determine the role of inflammation in impairing or restoring function in muscle and other tissues.
        3. Kinesiology
          • Better understand the interactions of muscle and muscle connective tissue and the potential role played by the associated structural molecules.
          • Improve understanding of how mechanical function of individual muscles determines energy use.
          • Determine how muscle differentially recruits fast and slow motor units.
      5. Pathophysiology
      6. Just as research into normal muscle physiology is likely to uncover new molecular treatment targets, an understanding of how specific molecular defects produce the abnormal phenotypes of muscle diseases will provide insights into normal muscle function.

        Broad areas of potential research directions include:

        1. Mechanisms of single gene muscle diseases
          • Identify the gene mutations associated with muscle diseases for which the cause is currently unknown.
          • Further characterize the genotype-to-phenotype correlations for muscle diseases.
          • Better understand the mechanisms of diseases caused by mutations in single genes, such as the muscular dystrophies and channelopathies. Through hypothesis-driven studies, characterize disease mechanisms to uncover potential therapeutic targets and to better understand normal muscle biology.
          • Elucidate how defects in post-transcriptional processing—including splicing, transcript modification, localization and transcript stabilization or degradation—contribute to muscle diseases.
          • Further understand mechanisms of muscle disease involving defects in post-translational processing such as glycosylation.
          • Examine the factors responsible for selective targeting of muscle groups or individual muscles by disease processes and the sparing of other muscles.
          • Identify compensatory gene products (e.g., utrophin for mutated dystrophin) and develop strategies to control their expression, accumulation, localization and activity.
          • Characterize the effects of modifier gene variations and epigenetic modifications on muscle disease onset, severity and progression.
        2. Muscle impairment associated with complex diseases and conditions
          • Explore the mechanisms that cause muscles and bones to atrophy during prolonged bed rest (often in the context of a critical illness such as cancer).
          • Investigate skeletal muscle changes in cachexia (as it occurs with diverse conditions including AIDS, cancer, chronic obstructive pulmonary disease, congestive heart failure, and end-stage renal failure).
          • Determine the causes and effects of age-associated sarcopenia at the subcellular, cellular and tissue levels.
          • Identify and characterize shared signaling pathways associated with downstream pathologies (such as weakness and muscle wasting) that are common to many genetic and acquired diseases.
          • Study disorders arising from environmental factors, including statin-induced myopathies; research the genetic and environmental factors contributing to these conditions.
          • Determine how muscle fatigue or pain is associated with chronic or acute diseases of other organ systems. Elucidate the mechanisms responsible for muscle pain.
          • Characterize the genetic and gene-environment interactions associated with complex muscle diseases such as inflammatory myopathies.
          • Study the role of muscle in inflammatory myopathies to facilitate the development of interventions that target the muscle and not just the immune system.
        3. Fibrosis and scarring
          • Elucidate the cellular and molecular events that contribute to, or prevent formation of, fibrosis and scarring during disease progression and in response to injury.
          • Determine whether muscle fibrosis is a reversible event and understand the steps involved in this process.
          • Characterize genetic modifiers of muscle fibrosis and scarring and test gene products as potential therapeutic targets or prognostic biomarkers.
    2. Muscle Biology and Diseases: Preclinical Translation and Therapy Development

      1. Development and use of model systems
      2. Cellular and animal models enable research into disease mechanisms and therapeutic target identification. Models also serve as testing grounds for candidate therapeutics.

        The NIAMS and other Institutes support infrastructure (e.g., through the Wellstone Muscular Dystrophy Cooperative Research Centers program) to facilitate studies that involve cellular and animal models.

        Broad areas of potential research directions include:

        1. Animal models for understanding disease mechanisms and testing therapeutics
          • Develop and characterize additional mouse models that more accurately reflect the genetics, pathophysiology or clinical phenotypes observed in muscle disease patients.
          • Make additional mid-size and large animal models to facilitate preclinical testing of candidate therapeutics in systems that are closer to the dimensions, biomechanical forces and immune responses seen in humans.
          • Develop additional animal models of muscle injury and regeneration, weakness, fatigue, pain and other common conditions affecting skeletal muscle.
          • Improve the research community’s access to animal models.
          • Make full use of published standard operating procedures and existing facilities for testing interventions in animal models of muscle diseases. Continue to document and publicize additional standard operating procedures where needed.
          • Further explore the use of xenograft models to study tissue derived from cells from muscle disease patients in a host animal.
        2. Human induced pluripotent stem (iPS) cells and other cells as disease model systems
          • Create human cell models to study disease mechanisms and pathophysiology.
          • Develop additional cell-based high-throughput assays suitable for screening libraries of small molecules and other bioactive compounds.
          • Establish human cell-based models for assessing candidate therapeutics.
          • Facilitate personalized medicine strategies by making cell models from individuals for the identification of compounds to which patients respond.
          • Study iPS cells from multiple patients to identify factors responsible for variations in responses to treatments.
      3. Preclinical therapy development
      4. There have been significant advances in recent years in the development of candidate therapies for muscle diseases, especially the muscular dystrophies. These include small molecules that act on cell or molecular processes, biologics such as antibodies or enzymes, gene and cell approaches, nucleic acids (e.g., oligonucleotides) as well as physical interventions such as vibration. Therapies are being developed by investigators in academic institutions and by small and large companies. In addition to the development of novel interventions, drugs that have already been developed for some other disease are now being tested for their potential use on muscle diseases (a process called drug repurposing). Some interventions that are being developed for rare muscle diseases, such as myostatin inhibitors, have the potential for applications in other muscle diseases and in more common conditions.

        Broad areas of potential research directions include:

        1. Repurposing and modifications of existing drugs
          • Explore the mechanisms of drugs that currently are used in the treatment of muscle diseases. For example, deciphering the genetic and molecular mechanisms by which corticosteroids benefit patients may enable the development of drugs that are more efficacious or cause fewer unwanted side effects.
          • Perform high-throughput screens of molecular libraries to identify compounds that can augment existing therapies for muscle diseases and disorders.
          • Pursue pre-clinical studies in muscle disease models for drugs approved for other diseases.
          • Study how exercise regimens and/or nutritional supplementation can impact the progression of muscle diseases and disorders or the response to other therapies.
        2. Developing novel interventions
        3. i. Small molecule drugs

          • Develop robust assays for use in high-throughput screens that take full advantage of the knowledge of mechanisms of muscle diseases to target important steps in the pathophysiology. Consider assays and screening strategies that go beyond the traditional chemical space.
          • Utilize available facilities and resources for high-throughput screening, chemical synthesis and modification, and pharmacology and toxicology testing. Examples include the NIH Molecular Libraries and Imaging Program and NCATS Bridging Interventional Development Gaps Program.
          • Create approaches to screening that are specialized for muscle biology.
          • Establish partnerships with companies and voluntary health organizations that increase the likelihood of successfully developing candidate therapeutics for testing in clinical trials.

          ii. Biologics

          • Explore the development of biologics for the treatment of muscle diseases, based on the activities of growth factors, extracellular matrix proteins, enzymes and other gene products.
          • Characterize the isoforms, subcomponents, metabolites and mechanisms of action of potentially therapeutic proteins and other biologics.
          • Broaden the use of enzyme replacement therapies beyond glycogen storage diseases, and develop strategies to prevent or manage immune response to enzyme replacement therapy.
          • Develop therapeutics that enhance muscle strength and resistance to fatigue.
          • Identify and test therapeutics that enhance or substitute for the effects of exercise training on skeletal muscle.

          iii. Gene therapies

          • Further characterize the properties of gene therapy vectors and serotypes to select for properties that facilitate the efficient delivery of therapeutic genes and minimize immune responses.
          • Continue to develop approaches to controlling gene activity (e.g., regulatory cassettes) that maximize the expression of therapeutic genes in specific target tissues.
          • Test routes and strategies for delivering gene therapies to muscle groups.
          • Develop a more thorough understanding of the immune responses to gene therapies. Use this knowledge to avoid or minimize immune responses following initial and repeated delivery of therapeutic genes.
          • Advance strategies for the preparation of gene therapeutics that increase the scale of production, reduce costs and optimize purity and activity.

          iv. Cell therapies

          • Characterize the abilities of growth factors, extracellular matrix molecules, scaffolds or transcription factors to stimulate the engraftment, survival, proliferation, and differentiation of cells that participate in muscle regeneration.
          • Compare the migratory and regenerative potential of different cell types to establish criteria associated with expansion, migration, differentiation, and stability of muscle cells and with long-term maintenance and function of muscle tissue for clinical studies.
          • Produce markers for tracking long-term outcomes of cell-based muscle therapies in animal models or in patients.
          • Study the immune response in muscle to transplanted cell types and factors in the environment of diseased or injured muscle that affect engraftment.
          • Explore strategies for the genetic manipulation of potentially therapeutic cells by viral vectors, genome editing technologies (e.g., CRISPR/Cas, TALENs), or other approaches to correct mutations or enhance their regenerative capacity.

          v. Molecular therapies (including oligonucleotides)

          • Continue to develop oligonucleotides and other strategies to edit or down regulate the expression of gene products with the goal of compensating for mutations and restoring the functions of proteins necessary for healthy muscle.
          • Further develop chemistries for the synthesis of molecular therapies and modifications to molecules that improve their efficiency for accessing skeletal muscle, heart and other affected tissues.
          • Further characterize the gene products resulting from exon skipping strategies and evaluate the ability of those products to restore normal muscle function.
        4. Behavioral and mechanical therapies
        5. Behavioral and mechanical therapies have the potential to improve outcomes in muscle diseases when used either instead of, or in conjunction with, pharmacological treatments. Exercise interventions and biomechanical treatments are included in this category. Some of these interventions, such as prescribed physical activity programs, could be tested in clinical studies without the need for prior animal studies, since the effects on human subjects may be quite different from that in animals. Other approaches such as vibration or other periodic forces would most likely benefit from animal studies to justify the safety, mechanisms of action and potential for efficacy in subsequent clinical trials.

          Broad areas of potential research directions include:

          • Leverage knowledge about the effects of mechanical stimuli on healthy and diseased muscle to develop biomechanical interventions such as vibration or period loading.
          • Study the mechanisms of exercise with the goal of developing physical activity-based interventions that patients are more likely to adhere to.
    3. Muscle Biology and Diseases: Clinical Translation

    4. Clinical translation for muscle diseases includes observational studies and clinical trials. Observational cohort studies serve several purposes including collecting data that may inform hypotheses regarding mechanisms of disease, developing biomarkers and outcome measures, acquiring data needed for the design of clinical trials and characterizing patients that would be candidates for participation in future trials. Clinical trials are needed to test the numerous interventions described above.

      1. Observational cohort studies of muscle diseases
        • Continue to characterize pharmacodynamic biomarkers from the blood and urine of muscle disease patients. These may include proteins, metabolites and nucleic acids (e.g., microRNAs).
        • Develop sensitive, accurate and robust assays for measuring proteins and other gene products found in muscle biopsies. These assays would be used to assess the restoration of these products in clinical trials.
        • Establish imaging biomarkers (e.g., as measured by MRI or ultrasound) that are non-invasive and provide information about the size, shape, structure, composition, physical properties and metabolic function of whole muscles or muscle groups. Further development of imaging methods can be facilitated by additional interactions among muscle disease researchers, imaging physicists and bioinformatics experts. The muscle research community should continue to adopt imaging advances from other fields such as neurology.
        • Continue to refine approaches for measuring muscle contraction, force production, musculoskeletal function, motor control and other physiological functions.
        • Integrate approaches such as elastography or electrical impedance myography into the development of biomarkers that reflect the physical properties of skeletal muscle.
        • Develop surrogate markers that can be quantified non-invasively and can predict changes in physical function, disease severity, the development of complications, or response to treatment.
        • Define outcome measures and markers that reflect meaningful changes in how the patient feels or functions. Studies to document their utility should also demonstrate the feasibility of including them in clinical trials.
        • Continue to develop patient reported outcome measures (PROs) that are suitable for use in specific muscle diseases by designing them with input from patients or by validating PROs developed for other diseases or conditions in people who have muscle diseases.
        • Use new biomarkers to facilitate disease diagnosis so that treatments to slow or halt disease progression can be started early when they are most helpful.
        • Establish cost-effective methods of diagnosing muscle diseases. A precise molecular diagnosis (i.e., exact information on the nature of the mutation) is essential for many of the potential therapies that are moving into clinical trials.
        • Integrate biomarker data into databases that include standardized, common data elements to facilitate comparisons between the biomarkers and physical functioning and clinical outcomes within the study and across other studies.
        • Conduct additional natural history studies to characterize patient phenotypic variations, disease course and comorbid conditions, especially for diseases that have not been previously studied in this way. Determine disease milestones that can be included in clinical trials of interventions that may block or reverse pathologies.
        • Investigate the genetic determinants of muscle mass and strength, efficient muscle repair, susceptibility to atrophy or disease, and response to treatment. This data can provide a foundation for developing personalized medicines. Although many muscle diseases result from single gene defects, genome-wide association studies offer opportunities to clarify the genetic bases for differences in disease manifestations and treatment responses.
        • Study environmental factors that may contribute to muscle diseases such as the inflammatory myopathies, and the mechanisms by which these factors interact with genetic variants and gene products.
        • Generate clinical patient data that will stimulate the development and testing of hypotheses regarding disease pathophysiology.
        • Evaluate patient transition to independence, level of care and access to care, and use this data to inform hypotheses related to the burden of disease and quality of health services.
        • Determine the incidence and prevalence of muscle diseases in racial and ethnic groups.
        • Explore how the care of patients with muscle diseases is affected by socioeconomic factors, geographic locations, and other demographic variables.
      2. Clinical trials for muscle diseases
      3. Numerous treatments of muscle diseases have demonstrated efficacy in animal models. Efficient testing of these promising interventions in patients will be required to realize effective treatments for various muscle diseases.

        Broad areas of potential research directions include:

        • Develop plans for clinical trials based on strong, reproducible data from animal studies or previous human studies.
        • Conduct trials that test drugs, biologics, cell or gene therapies, molecular therapies, exercise regimens, or biomechanical or behavioral interventions that have the potential to significantly advance treatment for muscle diseases.
        • Test for additive or synergistic effects among interventions that have demonstrated the potential for efficacy.
        • Combine knowledge gained through natural history studies and innovative trial designs to increase the likelihood of trials reaching clear conclusions, while minimizing the required number of participants.
        • Design clinical trials with outcome measures that are capable of following patients over the course of the disease so that both ambulatory and non-ambulatory patients can be included in the trial.
        • Develop strategies to lessen the burden of study participation on patients and family members.
        • Standardize outcome measures to allow for comparisons of treatments addressed in different studies.
        • Determine how interventions such as nutrition, exercise, and physical therapy work. Such knowledge may lead to better treatments and improved compliance.
        • Develop and test specialized “prescriptions” of exercises to maintain function or restore health. Even if a therapy such as exercise or stretching has only modest effects on symptoms, it could make a meaningful difference in patients’ lives if combined with other interventions.
        • Conduct trials with the highest likelihood of success first and develop strategies for managing patient participation in multiple trials, when possible. Consider patients as a rate limiting resource for clinical trials in rare muscle diseases.
        • Use predictive biomarkers and data on genetic modifiers to select for and stratify trial participants to increase the likelihood of collecting clinical trial results that are conclusive.
        • Pursue pharmacogenomic testing strategies that will allow personalized care with optimal treatment regimens.
        • In addition to testing interventions that address disease pathophysiology, conduct trials with behavioral interventions that address health services outcomes and issues of the daily living of patients with muscle diseases.

CONCLUSION

PLACEHOLDER

 

APPENDICES

    APPENDIX 1: OVERVIEW OF THE DEVELOPMENT PROCESS

    The FY 2015-2019 NIAMS Long-Range Plan follows the same structure as the FY 2010-2014 plan, with cross-cutting sections and disease- and tissue-specific topics. The FY 2014-2018 Strategic Plan for the Office of Disease Prevention (https://prevention.nih.gov/about/strategic-plan), the NIH Strategic Plan for Women’s Health Research (http://orwh.od.nih.gov/research/strategicplan/), and the soon-to-be released Action Plan for the Muscular Dystrophies (to be posted at http://www.ninds.nih.gov/about_ninds/groups/mdcc/) will serve as companion pieces to the NIAMS Long-Range Plan for FY 2015-2019, since the needs and opportunities presented in these documents are of particular interest to the NIAMS and other NIH components. In addition, the NIAMS will continue to partner with other NIH Institutes and Centers with whom we share common research interests. An NIH-wide list of strategic plans can be found at: http://report.nih.gov/strategicplans/index.aspx.

    The Institute solicited comments on how the long-range plan should be updated via a Request for Information (RFI) (Appendix 2) and gathered additional information through listening sessions with the community.

    The RFI was posted on the NIAMS website and in the NIH Guide for Grants and Contracts, and encouraged feedback from researchers, professional and patient advocacy organizations, health care providers, and patients and their families. The comment period spanned 90 days. Respondents were asked to provide input on the research needs and opportunities that should be modified because of progress over the last 5 years, and emerging research needs and opportunities that should be added to the Long-Range Plan. General comments were also encouraged. A total of 68 responses were received through the RFI, with many of the responses consisting of more than one comment.

    During December 2013, a series of six listening sessions were held with 80 individuals consisting of researchers and patients representing arthritis and rheumatic diseases, skin biology and diseases, bone biology and diseases, musculoskeletal biology and diseases, and muscle biology and diseases. Participants were encouraged to gather and share the views of the broader research community by consulting a diverse set of colleagues in advance of the listening sessions. In addition to providing input on their tissue- or disease-specific topic, they were asked about needs and opportunities that could be included in the cross-cutting sections on health disparities and training and career development. Five of the listening sessions were held via conference calls. The sixth session was an in-person meeting with K award mentors attending the NIAMS K Forum for Clinical Mentored K Awardees.

    Another component of the planning process at NIAMS includes yearly roundtable discussions, as well as an annual extramural program scientific retreat. Summaries of these meetings are posted on the NIAMS website and information was included in the Long-Range Plan where appropriate. See (http://www.niams.nih.gov/News_and_Events/Meetings_and_Events/Roundtables/ and http://www.niams.nih.gov/News_and_Events/Meetings_and_Events/Sci_Retreats/default.asp).

    Updates on the progress of the NIAMS Long-Range Plan for FY 2015-2019 were provided at the September 2013 and February 2014 Advisory Council meetings, and the draft plan was presented in June 2014. Additionally, in November 2013, the Institute provided a session at the NIAMS Coalition Outreach and Education Day on the purpose of the NIAMS Long-Range Plan, the process and timeline for revising the plan, and how organizations could be involved. The NIAMS Coalition is a group of over 90 professional and voluntary organizations interested in the Institute’s mission areas.

    [placeholder text to be updated when the plan is final]The draft plan was posted on the NIAMS website for X days and comments were solicited via an RFI published in the NIH Guide for Grants and Contracts (Appendix 2). All comments were reviewed carefully by Institute staff and incorporated into the document, as appropriate.

    After final clearance by the NIAMS Advisory Council in September 2014, the final version of the NIAMS Long-Range Plan for FY 2015-2019 was posted on the Institute’s public website and widely disseminated to NIAMS communities.[/placeholder]

    APPENDIX 2: REQUESTS FOR INFORMATION PUBLISHED IN THE NIH GUIDE FOR GRANTS AND CONTRACTS

    Request for Information (RFI) on the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Long-Range Plan for Fiscal Year’s (FY) 2015-2019

    ________________________________________

    Notice Number: NOT-AR-14-010

    Update: The following update relating to this announcement has been issued:
    • November 19, 2013 - See Notice NOT-AR-14-011. Notice of Extension of the Expiration Date.

    Key Dates

    Release Date: October 18, 2013

    Response Date: (Extended to January 15, 2014 per NOT-AR-14-011) Originally December 15, 2013

    Related Announcements

    None

    Issued by

    National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

    Purpose

    Background

    The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) is updating its Long-Range Plan to help guide the research it supports over the next five years. Public input on the topics to be included in the plan and suggestions regarding how to enhance the NIAMS research portfolio are critical initial steps in this effort. NIAMS leadership and staff will review and consider the comments as the Institute updates its Long-Range Plan.

    Information Requested

    Through this RFI, NIAMS invites feedback from researchers in academia and industry, health care professionals, patient advocates and health advocacy organizations, scientific or professional organizations, federal agencies, and other interested members of the public. Organizations are strongly encouraged to submit a single response that reflects the views of their organization and membership as a whole.

    Please provide your perspective on the following issues as they relate to the NIAMS Long-Range Plan for Fiscal Years (FY) 2010-2014:

    • Research needs and opportunities that should be modified because of progress over the past five years.
    • Emerging research needs and opportunities that should be added to the plan.

    NIAMS also welcomes your general comments, including those regarding the extent to which the FY 2010-2014 Plan has guided and encouraged the field.

    When commenting on a research need or opportunity, your comments can contain but are not limited to information pertaining to the following:

    • Description of the opportunity: Addressing an existing component of the FY 2010-2014 Plan that should be modified due to progress over the past five years, or a new opportunity for research not covered in the FY 2010-2014 Plan.
    • Rationale: The scientific evidence or clinical basis for the proposed change or addition and the anticipated impacts that accomplishments or advances related to this issue would have on the scientific community and human health.
    How to Respond

    Responses to this RFI must be submitted electronically using the web-based format at www.niams.nih.gov/About_Us/Mission_and_Purpose/long_range_form.asp. Responses will be accepted until December 15, 2013.

    Responses to this RFI are voluntary. Please do not include any personally identifiable or other information that you do not wish to make public. Proprietary, classified, confidential, or sensitive information should not be included in your response.

    This request is for information and planning purposes only and should not be construed as a solicitation or as an obligation on the part of the United States Government. The NIAMS or the NIH will not make any awards based on responses to this RFI, nor will the NIAMS or the NIH otherwise pay for the preparation of any information submitted or for the Government's use of such information.

    The NIAMS will use the information submitted in response to this RFI at its discretion and will not provide comments to any responder’s submission. Respondents are advised that the Government is under no obligation to acknowledge receipt of the information received or provide feedback to respondents with respect to any information submitted. The Government reserves the right to use any non-proprietary technical information in any resultant solicitation(s).

    Inquiries

    Please direct all inquiries to:

    David S. Zielinski, Ph.D. Office of Science Policy, Planning and Communications
    National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
    Telephone: 301-496-8271
    Email: niamslrpfeedback@mail.nih.gov

    THE SECOND RFI WILL BE INSERTED HERE

    APPENDIX 3: DEVELOPMENT TIMELINE FOR THE NIAMS LONG-RANGE PLAN: FISCAL YEARS 2015-2019

    2013 September Update to NIAMS Advisory Council on the development of the plan.
    October Request for Information posted in the NIH Guide for Grants and Contracts and on the NIAMS website for public input on research needs and opportunities that should be modified because of progress over the last 5 years and emerging research needs and opportunities.
    November Update to NIAMS Coalition on the development of the plan.
    December

    Listening sessions held as conference calls for:

    • arthritis and rheumatic diseases
    • skin biology and diseases
    • bone biology and diseases
    • muscle biology and diseases
    • musculoskeletal biology and diseases
    Listening session with participants at the NIAMS Forum for Clinical Mentored K Awardees
    2014 February Update to NIAMS Advisory Council on the development of the plan.
    June/July
    • Draft plan presented to NIAMS Advisory Council for review and input.
    • Draft plan presented to NIAMS Coalition for review and input.
    Draft plan and a Request for Information posted in the NIH Guide and on the NIAMS website to gather public input.
    August Review of public comments on draft plan and updates incorporated, as appropriate.
    September Final plan presented to NIAMS Advisory Council and posted on the Institute’s website.