Congressional Justification Narrative
FY 2006

February 2005 (historical)

Authorizing Legislation: Section 301 of the Public Health Service Act, as amended.

Budget Authority:

  FY2004 Actual FY2005 Appropriation FY2006 Estimate Increase or Decrease
BA $500,908,000 $511,157,000 $513,063,000 $1,906,000
FTE 220 220 220 0

This document provides justification for the Fiscal Year 2006 research activities of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, including HIV/AIDS activities. A more detailed description of NIH-wide Fiscal Year 2006 HIV/AIDS activities can be found in the NIH section entitled "Office of AIDS Research (OAR)."

Introduction

The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) supports basic, clinical, and epidemiologic research, research training, and information programs on many of the more common and debilitating diseases affecting the American people. Most of these diseases are chronic and many cause life-long pain, disability and disfigurement. These diseases include the many different forms of arthritis and other rheumatic diseases and numerous disorders of the musculoskeletal system and the skin that affect people of all ages, racial and ethnic populations, and economic strata. Many of the diseases within the mission of the NIAMS have a disproportionate impact on women and minorities. The NIAMS is committed to uncovering the bases of these gender, racial, and ethnic disparities and to devising effective strategies to treat or prevent them.

NIAMS Science Advances and New Initiatives

New Long Range Plan

In 2004, the NIAMS created and launched a process for formulating the next long range plan for the Institute. The current strategic plan is for the period of FY 2000-2004, and the new long range plan will cover the period FY 2005-2009. Planning panels were convened in September and October 2004 in the areas of research on arthritis and other rheumatic diseases, orthopaedics, bone biology and bone diseases, muscle biology and muscle diseases, skin biology and skin diseases, and cartilage and connective tissue biology and diseases. These planning panels included experts from the scientific and lay communities as well as scientists from the NIH Intramural Research Program. In addition, an e-mail note was sent to all NIAMS grantees and all of the voluntary and professional groups related to the mission areas of the NIAMS inviting their recommendations for scientific areas of needs, opportunities, and gaps. Furthermore, a notice was placed on the NIAMS Web site Home Page inviting suggestions and comments from the public on research needs, gaps, and opportunities. All of this input will be considered as the NIAMS drafts our next long range plan.

New Translational Research Centers

The NIAMS undertook a significant evaluation and planning activity last year. In order to ensure that our Specialized Centers of Research (SCOR) program was taking full advantage of the tremendous opportunities in translational research, the NIAMS formed a panel of experts from across the disciplines in our mission areas and asked these outside experts to evaluate our SCOR program. As a result of their careful analysis and thoughtful report, the NIAMS is phasing out the SCOR program. In FY 2006, the Institute will launch a new mechanism that is known as Centers of Research Translation (CORTs). The new CORTs will pull together basic and clinical researchers in a targeted and organized way, and will put the emphasis on translating research results from basic research to clinical research as well as translating the findings from clinical research to improve and focus the approaches used in basic research - all with the goal of improving public health. The translational studies at these new Centers are expected to maximize the power and benefits of translational research.

The NIH Roadmap for Medical Research

The NIAMS is pleased to partner with other NIH components in the many dimensions of the NIH Roadmap. It has been a little over a year since the NIH Roadmap was launched, and the potential to increase and synergize research at the molecular level and in clinical studies is already being realized. The NIAMS has responsibility for the management of an initiative for a patient-reported outcomes measurement information system - or PROMIS - network, an integral part of the Re-engineering the Clinical Research Enterprise component of the Roadmap. The goal of this initiative is to develop ways to measure patient-reported symptoms such as pain and fatigue and aspects of health-related quality of life across a wide variety of chronic diseases and conditions. One dimension of the PROMIS initiative is to develop a publicly available computerized adaptive test for the clinical research community. Many diseases involve pain, fatigue, and other difficult-to-measure quality of life outcomes, and the development of a test to measure changes in these symptoms will enhance clinical outcomes research and ultimately clinical practice. The Institute will consider ways to enhance the NIAMS-specific dimensions of the PROMIS initiative in FY 2006.

Cross-cutting Areas: Autoimmunity and Behavioral Research

There are a number of disciplines and foci of research that cut across the NIAMS, and indeed much of the NIH. Autoimmunity is one such cross cutting area. While medical research has resulted in significant progress in our understanding of autoimmune diseases, it remains a puzzle why, in some patients, the body's own cells turn against the body's own tissues. A number of arthritic and skin diseases in the research mandate of NIAMS have their origin in autoimmunity, and research in this area is integral to the Institute. Diseases in this category include systemic lupus erythematosus (SLE or lupus), rheumatoid arthritis, Sjogren's syndrome, alopecia areata, scleroderma, and many blistering skin diseases - all potentially devastating chronic diseases that exact a huge toll in human suffering and economic costs. Active areas of research include studies that are focused on identifying causative agents or components of the body involved in autoimmune disease.

The body has both innate and adaptive immune systems, and they are in a delicate balance with constant interaction. The innate immune system is the series of cells and factors that protect people from a variety of non-specific materials that may enter the body inadvertently. The adaptive immune system relates to the specific responding elements, such as antibody and memory T cells, that arise after immunization and vaccination and increase protection to the particular material to which the individual was exposed. Rather than act separately and sequentially, it has become apparent that there is an interplay between the innate immune system and the adaptive immune system. In order to stimulate research in this area, the NIAMS issued a solicitation to the research community indicating our interest in grant proposals that would increase our understanding of the role of innate immunity in the cause and disease course of autoimmune rheumatic diseases. Understanding the role of the innate immune system in the earlier events in the course of autoimmune diseases could lead to prevention of end organ damage and earlier intervention in autoimmune rheumatic diseases. There was a robust response to this solicitation and the NIAMS funded eight highly meritorious research projects. Autoimmune rheumatic diseases carry significant morbidity and enormous health care costs, and there is great scientific and public health value in identifying new targets for intervention in the early stages of disease. The projects funded in response to this solicitation have the potential to identify such targets.

A second cross cutting area is behavioral research. We know that biopsychosocial perspectives and approaches to research can contribute to our understanding of the etiology, course, and outcomes of rheumatic, musculoskeletal, and skin diseases, but behavioral research in these disorders has been relatively limited. There exists a fundamental need to develop better collaboration among behavioral scientists, physicians, and basic scientists with interests in or relevant to diseases of bones, muscles, joints, and skin. Providing interdisciplinary training opportunities will ultimately enhance the quality and quantity of interdisciplinary research in these diseases. To increase integration of behavioral and biopsychosocial approaches into research on bones, muscles, joints, and skin, the NIAMS issued a solicitation for research in this area, and made awards to three projects that will increase training and career development in biopsychosocial rheumatic, musculoskeletal, and skin diseases research.

The most distressing and disabling aspects of rheumatic and musculoskeletal diseases for most patients are chronic fatigue, pain, and cognitive dysfunction. Behavioral scientists and neuroscientists are uniquely qualified to investigate and develop interventions for these phenomena. Investing in biopsychosocial research is expected to provide new insights into the etiology and course of these diseases, and has great potential to result in more effective approaches to disease prevention and management.

Arthritis and Other Rheumatic Diseases

State-of-the-Art Genomics Project to Examine Gene Expression Patterns in Pediatric Arthritis

The NIAMS has launched a state-of-the-art genomics project that is examining gene expression patterns in children with arthritis, to uncover gene expression patterns that contribute to the development of pediatric arthritis. It is supported by a partnership that includes the NIAMS, a chapter of the Arthritis Foundation, and the Schmidlapp Trust. By using DNA microarrays -- small silicon chips that contain tiny amounts of thousands of known genes -- to carry out a technique called gene expression profiling, these researchers are analyzing thousands of genes in the blood, fluids and tissues of children newly diagnosed with various types of pediatric rheumatic diseases such as juvenile rheumatoid arthritis or JRA, juvenile ankylosing spondylitis or spinal arthritis, and related immune disorders. Identifying gene expression patterns - groups of genes that are "turned on" - for different types of childhood arthritis will help to improve diagnosis and to predict disease severity for affected children. Gene expression data from four related projects will be stored in a tissue repository and analyzed in a gene informatics center. Storage and analysis of genetic information will help to create a large-scale database that will be a key factor in identifying disease pathways and developing new therapies for pediatric rheumatic diseases. The information learned from this study, including creating a national genome expression database available to the entire scientific community, will accelerate research discoveries in pediatric arthritis.

Scientists Find Gene Variant That Increases Susceptibility to Juvenile Rheumatoid Arthritis

A genetic variation within the interleukin-6 (IL-6) gene increases susceptibility to systemic juvenile rheumatoid arthritis (JRA), according to researchers funded by the NIAMS and the Arthritis Research Campaign. Researchers from around the world collaborated to collect DNA samples from children with JRA and from one or both parents. The transfer of genetic information from parent to child was analyzed, and the scientists found that children who developed JRA were more likely to inherit the variant form of the IL-6 gene from their parents. Children who developed systemic JRA at age 5 or older showed significantly higher levels of this variant compared to the children who developed the disease before age 5. These findings suggest that there may be distinct genetic profiles for the disease that result in differences in age of onset and disease severity. Continuing to uncover disease-associated genes may lead to health care providers having clinically useful subgroupings of systemic JRA.

A New Study to Show How Rheumatoid Arthritis Patients Rate Improvement Change

A new clinical study that has recently been launched in the Intramural Research Program of the NIAMS is seeking to determine how people with rheumatoid arthritis evaluate improvements in disease symptoms. The study will examine how much of an improvement in pain, stiffness, function and other symptoms is needed before patients consider the change important. Using these patient-based criteria, doctors will know if a new treatment has a high likelihood of being rated by patients as helpful or not.

Synthetic Peptide May Help Correct Damaging Immune Responses in Rheumatoid Arthritis

Rheumatoid arthritis is an autoimmune disease, and treatment often involves powerful drugs that will suppress the immune system. While these drugs may be able to keep the disease better controlled, in suppressing the immune system, they may leave the patient especially vulnerable to infection. Researchers supported by the NIAMS have found a potential treatment to suppress the abnormal, self-directed immune response that is responsible for rheumatoid arthritis without hampering the body's ability to fight bacteria and viruses. The treatment is a synthetic peptide - a chain of amino acids - called dnaJP1.

Previously, researchers had found that in rheumatoid arthritis, the immune system is confused by a sequence of amino acids called human leukocyte antigen (HLA) produced on cells' surfaces during an immune response. In many patients with rheumatoid arthritis, HLA shares a specific, characteristic sequence of amino acids. In healthy people, HLA works to help keep the body's immune response under control, but in rheumatoid arthritis, the antigen fails to work properly, resulting in an immune response that causes damage. To help prevent that damaging response, researchers focused their study on the protein called dnaJP1 that the body uses to initiate the response. A particular section of that protein - the dnaJP1 peptide - has the same characteristic amino acid sequence as that found in patients with rheumatoid arthritis. By giving patients a synthetic version of the dnaJP1 peptide, the researchers suspected they could teach the immune system to tolerate this specific amino acid chain instead of seeing it as foreign and attacking it.

In an initial study in a group of patients with rheumatoid arthritis, blood tests showed that dnaJP1 resulted in normal immune system responses. The results of this initial study form the basis of a new larger study that will also assess patients' symptoms and evaluate the effects of dnaJP1 on the immune system and physical exams to determine if changes in the immune system result in a reduction in symptoms. The National Institute of Allergy and Infectious Diseases, the Royal Netherlands Academy of Arts and Sciences, and the Dutch Organization for Scientific Research also helped fund this study.

Family Links in Fibromyalgia

Fibromyalgia is a disorder of unknown etiology that is defined as widespread pain of at least 3 months duration in combination with tenderness at 11 or more of 18 specific tender point sites on the body. Additional characteristic symptoms of fibromyalgia include fatigue, sleep disturbance, and morning stiffness. Results of previous family studies have suggested that fibromyalgia might cluster in families, and might cluster together with major mood disorders in families. NIAMS-supported researchers undertook a controlled family study and found that fibromyalgia was strongly aggregated in families. In addition, both tender point count and total muscle pain scores were strongly associated with fibromyalgia in families, and this association was independent of the presence of major mood disorders in the families. Furthermore, an elevated presence of mood disorders was found in the relatives of fibromyalgia patients. Aggregation of fibromyalgia in families suggests that genetic factors may be involved in the etiology of fibromyalgia and in pain sensitivity, and mood disorders and fibromyalgia may also share some of these inherited factors. In November 2004 the NIAMS supported a workshop on fibromyalgia, with a view to the next scientific advances. The workshop provides clinicians with a conceptual grounding of the current state of the science in understanding the factors contributing to fibromyalgia.

A New Study of Hematopoietic Stem Cell Transplantation for Severe, Treatment-Resistant Lupus Launched

Researchers at NIH, under the leadership of the NIAMS Intramural Research Program, have launched a study to determine whether a therapy using transplantation of hematopoietic stem cells, blood stem cells found in bone marrow, can produce long-term remission for patients with severe, treatment-resistant lupus. The study will include a basic research component to examine the roles of various white blood cells, including the two major components of the immune system - T cells and B cells -- in triggering lupus.

Many patients with severe forms of lupus have limited treatment options that may offer only temporary relief of symptoms and no disease regression. For these patients, stem cell transplantation therapy may offer hope for a normal functioning immune system. Severe forms of lupus can devastate patients, causing pain, fatigue, depression, and in some cases, premature death. Patients who enter this study will have been treated, to no avail, with high doses of immunosuppressant drugs, which decrease immune function. Researchers believe that by combining immunosuppressant treatment with stem cell transplantation, they can create a new immune system that does not attack the body's healthy cells. Researchers in the National Cancer Institute, the National Institute of Neurological Disorders and Stroke, and the National Institute of Diabetes and Digestive and Kidney Diseases are collaborating in this effort.

The Immune System's B Cells are Targeted in Lupus and Rheumatoid Arthritis

After activation and differentiation, B cells become antibody-producing cells. In patients with autoimmune diseases such as rheumatoid arthritis and lupus, some B cells migrate to the inflamed kidneys and the tissue lining the joints, the synovium, and contribute to the inflammatory process. Recent research demonstrates that the depletion of peripheral blood B cells that occurs when an anti-CD20 antibody (rituximab) is given to patients with autoimmune diseases reduces disease activity even though the levels of antibodies produced by B cells in the serum remain unchanged. Studies in which rituximab was given to patients showed that the rituximab-induced B cell depletion resulted in a significant improvement in lupus disease activity even in the absence of substantial reductions of antibody levels. These research reports support the proposition that B cells have an antibody-independent role in the pathogenesis of rheumatoid arthritis, lupus, and other systemic autoimmunity in general, and they can be targeted for therapeutic interventions.

Additional Insights into Molecular Mechanisms of Brain Changes in Lupus Revealed

The manifestations of lupus are diverse - it can affect many parts of the body, including the joints, skin, kidneys, heart, lungs, blood vessels, and brain. A team of researchers supported by the NIAMS focused on the involvement of the nervous system in some people with lupus, and reported significant advances in our understanding of the molecular mechanisms involved in changes that can occur in the brains of people with lupus. These researchers previously reported that the antibodies that attack the DNA of people with lupus can also attack molecules that bind a particular neurotransmitter (glutamate) involved in nerve cell activity. These same antibodies can cause death of the nerve cells, and they are present in the fluid of the brain and spinal cord, possibly affecting brain function. While researchers had previously documented cognitive dysfunction in some patients with lupus, it had not been clear what mechanism was involved in this dysfunction. The Institute released a solicitation for applications on neuropsychiatric lupus in an effort to stimulate additional study of the neurological and psychiatric syndromes associated with this chronic disease, including cognitive, behavioral, affective and motor manifestations. One project that was funded through this solicitation has recently reported additional insights into neuropsychiatric lupus. In this research, it was shown that mice can be induced to produce antibodies to a particular receptor on nerve cells in the brain. These antibodies can be measured in the blood. The antibodies do not cause nerve damage unless the blood-brain barrier is broken and the antibodies have access to the brain. When the blood-brain barrier was broken, these antibodies bound to specific areas in the brain and nerve cell death was demonstrated. Behavioral tests in these mice revealed specific cognitive dysfunction as well. Furthermore, if a drug was given that blocked the brain receptor at the time of the breakdown of the blood-brain barrier, no neuronal damage or apparent cognitive dysfunction was evident. These results have defined a mechanism for the occurrence of neuropsychiatric lupus. In addition, the nature of the brain damage caused by these antibodies can be detected without the need for a brain biopsy. Protecting this brain receptor from the damaging effects of this particular antibody is a novel approach to the treatment of neuropsychiatric lupus that has emerged from this research.

Biomarkers for Lupus

The NIAMS is actively supporting research to identify and validate biomarkers for lupus. For example, the Institute supports the Autoimmune Biomarkers Collaborative Network, a group that is using cutting edge technologies, such as gene expression profiling with DNA microarrays, to develop biomarkers for lupus. These new technologies may assist in the diagnosis of lupus, help physicians better guide and manage therapy, and provide information on the course of disease for lupus patients. In addition, in the fall of 2003, the NIAMS intramural program held a meeting to discuss the development and validation of biomarkers of lupus. Participants included a number of clinical and basic scientists from the lupus research community as well as representatives from the NIH, the FDA, and voluntary organizations. A key focus of the day was discussion of the barriers to biomarker development in lupus. The participants also underscored the need to identify the potential biomarkers for lupus that should be examined, develop methodologies to validate potential biomarkers, identify the infrastructure necessary to identify lupus biomarkers, and develop methods to collect and analyze large amounts of clinical material. It was recognized that biomarkers have significant value in clinical settings in facilitating the development and use of new therapies. The NIAMS Intramural Research Program has initiated a program to identify and validate lupus biomarkers.

Biomarkers for Osteoarthritis

Osteoarthritis is the most common type of arthritis. Researchers have been hampered by the fact that existing indices of osteoarthritis present a sometimes confusing and relatively insensitive index of disease onset and progression. Discovery of new and more sensitive biomarkers for onset and progression of osteoarthritis (such biomarkers could be biochemical or structural but should be related to pain and loss of function in osteoarthritis) is a significant research need, but undertaking such a complex discovery process was beyond the scope of what any NIH institute or pharmaceutical company could undertake alone. The NIAMS partnered with the National Institute on Aging (NIA), several other NIH components, and three pharmaceutical companies in establishing the Osteoarthritis Initiative, a public-private partnership aimed at developing clinical research resources that support the discovery and evaluation of biomarkers and surrogate endpoints for osteoarthritis clinical trials. For the first time, a public-private partnership is bringing together new resources and commitment to help find biological markers for the progression of osteoarthritis. Patient recruitment is actively underway and by the end of FY 2004, more than 1,000 patients had been recruited. All data and images collected will be available to researchers worldwide to help quicken the pace of scientific studies and biomarker identification. It is expected that this consortium can serve as a model for future endeavors that link the public and private sectors.

A second, related initiative is the Osteoarthritis Biomarkers Network. To hasten the pace of discovery of molecular biomarkers for osteoarthritis, the NIAMS established this network and awarded grants to institutions in the United States and Sweden. For the first time, researchers who have been individually studying osteoarthritis biomarkers will share clinical, biological and human resources. Through the network, investigators will learn more about joint destruction by identifying and monitoring biomarkers in blood, urine, and joint tissues. It is hoped that this will provide the clues needed to define the stages of disease on a more consistent and reliable basis. Investigators in the network will work collaboratively and share resources for the development, evaluation, and validation of biochemical markers for osteoarthritis onset, severity, progression, and response to treatment. The goal is also to speed the process for identifying biomarkers so that people at various stages of the disease can be identified before they progress to significant symptoms of pain and joint deterioration.

Musculoskeletal Biology and Musculoskeletal Diseases

Scientists Discover HIV Medication May Preserve Bone

For people infected with the HIV virus, treatment with highly active antiretroviral therapy, such as HIV protease inhibitors that block an enzyme used by the virus, has been associated with unexplained bone loss. Scientists funded by the NIAMS have begun to learn how such agents affect bone, and have discovered that one HIV drug -- ritonavir -- may actually preserve bone. In basic research studies, scientists looked at the impact of ritonavir and another commonly used protease inhibitor, indinavir, on the formation and function of bone-building cells called osteoblasts as well as bone-resorbing cells called osteoclasts. Under normal circumstances, the two types of cells work together in a balanced process to keep bone strong and healthy. But when bone resorption by osteoclasts outpaces bone formation by osteoblasts, the result is that old bone breaks down faster than new bone is being built. Bones begin to lose mass, sometimes to the point that they become brittle and subject to fractures. In HIV patients taking protease inhibitors, the scientists suspected that bone resorption outpaced formation. What their studies revealed was that indinavir did nothing to the bone-resorbing osteoclasts, but ritanovir did. In fact, ritonavir seemed to affect osteoclast differentiation as well as stopping the ability of mature cells to resorb bone. Scientists next tested these findings in an animal model, and they injected parathyroid hormone or PTH (a standard technique to stimulate bone resorption) into a large number of mice. The scientists then gave ritonavir to some of the PTH-treated mice. When they later examined the bones of both groups of mice as well as mice that had neither treatment, they found that, as expected, the mice given parathyroid hormone had more osteoclasts than untreated mice. However, in the mice given ritonavir as well, osteoclasts were shut down. These animal studies suggest that ritonavir is suppressing bone loss. These intriguing studies in animal models provide many promising avenues of research to be pursued in the future to shed light on bone biology and how the balance in bone is altered in various diseases.

Dental X-rays Can Predict Changes in Bone Micro Architecture

Osteoporosis is characterized by low bone mineral content and breakdown of the micro architecture of the bone scaffold that results in increased bone fragility and fracture. There is a need for improved methods for screening for osteoporosis and for those at high risk for subsequent fractures. Recent reports have shown that bony regions of conventional dental radiographs may be useful in the evaluation of bone micro architecture and changes over time can be followed. When these analyses were applied to women with osteoporosis and women without osteoporosis, it was possible to distinguish the bone changes between these two groups. Women with osteoporosis had altered patterns of trabecular bone, the honey comb-like bone found in the jaw and spine and at the end of long bones, compared to those without osteoporosis. This suggests that dental radiographs could provide a reasonable and widely available screening method to assess low bone mineral and micro architectural changes in bone. These methods could also provide a more sensitive tool for evaluating the efficacy of drugs in modification of bone micro architecture.

Genetic Analysis in Mice Reveals New Drug Target for Osteoporosis

Although many genes are already known to influence bone mass, there is strong evidence that other genes, still unidentified, also influence bone mass and fracture risk. Identifying these genes is challenging, especially in human populations, because humans are genetically very diverse. The analysis is simpler in mice, because genetically uniform laboratory strains of mice are available. Much evidence indicates that bone physiology in mice is similar to that of humans. For that and other reasons, there is a good chance that genes identified in mice will serve to identify human genes that have similar physiological roles. Working with two mouse strains that have very different bone mineral density (BMD), scientists have recently found that naturally occurring variation in a gene called Alox 15 accounts for a significant part of the difference in BMD. By breeding mice from the two strains, researchers had previously generated hybrid mouse strains with a wide range of BMD. Analysis of the hybrid mice suggested that a number of genes could influence BMD, but did not actually identify any of the genes. Now, using recently developed tools for detailed study of gene activity, the investigators have identified one of the genes as Alox15, a gene that was not previously recognized as important for the skeleton. Because Alox15 is known to be involved in the metabolism of certain compounds related to fats, this discovery has implications for how different metabolic pathways interact to affect bone. In fact, drugs have already been developed that interfere with Alox15 activity, because of the gene's possible involvement in heart disease and other health problems. These drugs were found to prevent bone loss in rats, confirming that Alox15 has an important influence on bone mass.

The acquisition and maintenance of bone mass are important determinants of the risk for fracture, especially in women after menopause. The discovery that the Alox15 gene can influence bone mass in mice is a guide to new ways of preserving bone mass in humans. There are two genes in humans with activities similar to that of Alox15, suggesting that one or both of these might be valuable therapeutic targets. In addition, the discovery of Alox15's influence on bone mass suggests that a previously unsuspected metabolic pathway may be important for skeletal health. Studies of this pathway could yield additional clues to the prevention of fractures.

Alendronate and Calcitriol Reduce Bone Loss after Heart Transplantation

Researchers comparing the action of these bone active drugs in a clinical trial have found that both reduce the degree of bone loss commonly seen in the first year following transplant surgery. Heart transplant patients have been shown to be particularly at risk for osteoporosis and fractures due to the type of drugs they take to suppress rejection of the new organ. The drug alendronate, however, which reduces the activity of cells that cause bone loss, was judged to be more clinically useful because it is more simple to monitor and doesn't affect the fragile metabolism of the recovering transplant patients. Calcitriol, a synthetic substance similar to vitamin D, helps regulate calcium metabolism in the body but needs to be carefully monitored and may be more difficult to use in patients with complicated medical situations like transplants.

New Research Grants Awarded to Study Mechanisms of Mineralization of Bone

Mineralization of bone is critical for the hardness and strength that support our weight and resist fracture. A number of serious disorders are caused by mineralization defects, particularly affecting children. There is also increasing evidence that variation in the quantity or quality of mineralization is a factor in the increased risk for fracture in older people. Yet the mineralization process is poorly understood, partly because few biological models reflecting defects in the process have been available. The NIAMS issued a Request for Applications in this area and awarded two outstanding grant proposals in 2004. The newly awarded grants take advantage of recently developed models that have the potential to illuminate the mineralization process. The models are based on genetically modified mice, in which specific genes have been inactivated, with the consequence that the normal mineralization process is disrupted. These investigations seem likely to reveal new aspects of bone formation and maintenance, and may suggest new targets for the development of drugs to treat a variety of bone disorders.

Functional Outcomes Following Trauma-Related Lower Extremity Amputation

Motor vehicle accidents are a common cause of injury and death, and this is particularly true if the victims are either pedestrians or motor cycle riders. Injuries to the legs are especially common, and may require amputation of the injured portion of the leg. Researchers recently followed a group of patients who underwent above-the-knee amputations at a trauma center to study functional status as well as pain, degree of independence in daily tasks, walking and climbing and other measures. There were no significant differences in function between below-the-knee and above-the-knee amputees, except for faster walking speeds in below-the-knee amputees. However, through-the-knee amputees had lower function than the other two groups of amputees, and physicians were less satisfied with the clinical, functional, and cosmetic recovery of patients with a through-the-knee amputation. The results of this study underscore the need for controlled studies that examine the relationship between levels of amputation and functional outcomes in this population, and secondarily, the relationship between the type and fit of prosthetic devices for these respective levels of amputation, and functional outcomes.

Story of Discovery

Medical Research has Resulted in Improved Length and Quality of Life for People with Joint Replacements. Arthritis is a major contributor to impairment of daily functions and disability in affected people, and it accounts for a large proportion of hospitalizations and health care expenditures of the elderly. A major advance in the treatment of joint degenerations is the success of total joint replacements, procedures in which the damaged joint surfaces are replaced with metal and/or plastic components. Studies over the last decade have documented the cost effectiveness of these procedures, and coupling cost savings with the marked improvement in functional abilities and quality of life means that total joint replacements are making a huge difference in the lives of many Americans.

The tremendous success of this procedure is borne out by follow-up studies of patients who have undergone total joint replacements. The NIAMS supported a 25 to 35-year follow-up of patients who received conventional total hip replacements that were cemented and who were less than 50 years old when surgery was performed. This study showed that less than one-third of the original total hip replacements had to be revised or removed, and more than two-thirds of the original group who had a total hip replacement were functioning well years later. A second study determined that the timing of total joint replacement affects clinical outcomes among patients with osteoarthritis of the hip or knee and suggested that total joint replacement in patients should be done early, before patients experience significant decline of function.

NIH Consensus Development Conferences provide vital information to patients and their health care providers regarding joint replacements. While enthusiastically supporting total hip replacement as a cost-effective and quality of life enhancing therapy, a 1994 Consensus Conference on Total Hip Replacement highlighted concerns about loosening of the artificial joint and the effects of the implant on the body. Deterioration of prosthetic implant materials is a major factor limiting the durability and longevity of total hip replacement. Periprosthetic osteolysis -- literally the disappearance of bone around the implant -- is the most frequent complication of joint replacement.

The cause appears to be related to the body's inflammatory response to debris from the implants themselves. This can result in implant loosening, which can be painful, and ultimately can lead to implant failure and necessitate revision surgery. Such surgery is more difficult to perform, is more costly, and has poorer results than the primary replacement. In basic research laboratories, models were developed to study the effects of different wear particles, including titanium and polystyrene, on bone collagen. Research has provided important information on the roles of decreased bone synthesis as well as inflammation in response to implant particles. The Conference served to stimulate research that led to the development of improved cementing techniques, newer fixation techniques for both cemented and cementless implants, and metallurgic processing to lessen the incidence of breaks in the implants. The NIAMS supported a number of basic, clinical, and translational research studies over the last decade to better understand metal release, transport, storage, and excretion of metallic wear debris in patients who have undergone total joint replacement surgery.

A more recent Consensus Development Conference on Primary Total Knee Replacement (December 2003) concluded that for persons suffering from intractable and persistent knee pain and disability, total knee replacement surgery is a safe and cost-effective therapy that restores mobility and alleviates discomfort. Over 20 years of follow-up data indicate that the procedure is successful in the vast majority of patients.

If we look back over the last several decades at total joint replacement, the effectiveness of this treatment is evidence of the success of public and private support of research in many dimensions including biomaterials, biomechanics, and medical implant science. One of the genuine success stories of medical research is the replacement of joints that have degenerated. Hundreds of thousands of affected Americans have benefited from advances in total joint replacements, and the new joints have improved function in daily life, reduced pain, and increased the quality and productivity of their lives.

Muscle Biology and Muscle Diseases

Fundamental Research on Muscle Biology

Skeletal muscle is necessary for movement and well being. It visibly responds in size and tone to use or disuse. Its characteristics affect how the body uses energy and its demands require adaptations of the cardiovascular system. Chronic inactivity of skeletal muscle is associated with systemic metabolic dysfunction and diseases such as obesity and insulin-resistant diabetes. A major goal of muscle biology research is to understand skeletal muscle as an integrated whole-body system. Current NIAMS-supported research efforts include the combined use of cell physiology, genetic techniques, biophysics, whole animal measurements, and computer modeling to generate fundamentally new theories of how muscular systems are designed and function to maintain health.

Muscular Dystrophy

Muscular dystrophy refers to a group of genetic diseases characterized by progressive weakness and degeneration of the skeletal or voluntary muscles which control movement. The muscles of the heart and some other involuntary muscles are also affected in some forms of muscular dystrophy, and a few forms involve other organs as well. Duchenne muscular dystrophy is the most common form of muscular dystrophy to affect children. It is caused by mutations in the dystrophin gene and results in repeated cycles of muscle damage and insufficient muscle regeneration, leading to gradual replacement of muscle by fibrous tissue.

Gene Therapy Reaches All Damaged Muscles in Muscular Dystrophy Mouse

Researchers supported by the NIAMS have recently reported that a particular method of gene therapy was able to reach all damaged muscles in a muscular dystrophy mouse, with implications for delivering genetic therapy for muscular dystrophy and perhaps other diseases of the muscle or heart. This research showed for the first time a method by which a corrected gene for dystrophin - a protein found in normal muscle tissue -- can be delivered systemically to affected muscles of a mouse with a disease that resembles Duchenne muscular dystrophy. NIAMS funded researchers found that by giving a single injection of an adeno-associated viral (AAV) vector - this is a viral "vehicle" carrying a mini-dystrophin gene - into the bloodstream, they were able to deliver levels of dystrophin that significantly improved muscle function. These included muscles of the heart and legs.

Previous work showed that muscular dystrophy could be prevented from occurring in a mouse model of the disease by replacing the gene for dystrophin, which is defective in people with the Duchenne form of the disease, with a corrected copy of the gene. In addition, injecting a new dystrophin gene into a single diseased muscle could improve the health of that one muscle. However, until now, no one had found a method in which a new gene could be delivered to all muscles of an adult animal, including muscles that had already developed muscular dystrophy. Researcher injected the vector carrying the gene as well as using vascular endothelium growth factor - a molecule that allows the vector to move through the blood vessel walls into the muscles The vascular endothelium growth factor binds to receptors on the surface of cells that line blood vessels and make them more permeable so that viral particles from the blood stream move into muscle and other tissues, bind to cells, and deliver the new dystrophin gene (this gene has been engineered for expression only in skeletal muscle cells). Thus, the researchers were able to get the genes to all of the intended sites -- the damaged muscles in this model of muscular dystrophy.

This finding gives a significant boost to the many efforts to find answers for muscular dystrophy, for which there is no effective treatment. Additional animal model research is needed to determine whether the dystrophy can be completely eliminated. Researchers suspect that the earlier this treatment is introduced, the better the results will be, and this is currently an area of active study. The hope is that this advance can be applied to other muscular dystrophies as well. The Muscular Dystrophy Association partnered with the NIH in funding this research.

Protein May Hold Key to Repair of Damaged Muscles

For people with muscular dystrophies, treatment is usually limited to physical therapy to prevent painful muscle contractures, orthopaedic appliances for support, and orthopaedic surgery to help correct some of the problems caused by the disease. But scientists in the NIAMS Intramural Research Program and their colleagues are actively seeking to develop better options, including treatments to promote the regeneration of damaged muscles.

These researchers have suggested that treatments could be based on a protein called follistatin, which they have discovered plays a critical role in the growth and regeneration of adult skeletal muscle cells, and/or a group of chemicals called histone deacetylase (HDAC) inhibitors that help follistatin do its job. This study revealed that the level of follistatin is significantly elevated in muscle cells when they are treated with HDAC inhibitors. HDAC inhibitors stimulate the formation of mature muscle cells from immature precursor cells. When follistatin levels are reduced, however, HDAC inhibitors no longer stimulate adult muscle growth, the researchers found. The regeneration activities of the HDAC inhibitors appear to function only in skeletal muscle, since follistatin is not stimulated in other cells tested. In animal studies, administering an HDAC inhibitor produced signs of muscle regeneration in regions of injured skeletal muscle tissue. This new study establishes for the first time that follistatin promotes the recruitment and fusion of immature muscle cells to pre-existing adult muscle fibers. These findings suggest that follistatin is a promising target for future drug development of muscle regeneration. HDAC inhibitors, by stimulating, follistatin, could be pharmacologically useful as stimulants of muscle regeneration.

Other Muscular Dystrophy Programs and Activities

Working in collaboration with the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Child Health and Human Development (NICHD), the NIAMS has been actively engaged in continuing to implement the Muscular Dystrophy Community Assistance, Research, and Education Amendments of 2001 (the MD-CARE Act), to boost research and training related to all forms of muscular dystrophy. One item included in the MD-CARE Act was the establishment of a trans-NIH coordinating committee to oversee federal muscular dystrophy research and education activities. The Secretary of HHS selected the Director of the NIAMS to serve as the chair of the new Muscular Dystrophy Coordinating Committee (MDCC) and in September 2004 the MDCC released the Muscular Dystrophy Research and Education Plan for the NIH. The plan was designed as a working document for the entire muscular dystrophy community and includes five major areas: understanding the mechanisms of disease; screening and diagnosis; treatment strategies; living with muscular dystrophy: rehabilitation, quality of life, and psychosocial issues; and research infrastructure needs. In addition to ongoing muscular dystrophy research, in FY 2003, NIAMS, along with NINDS and NICHD, each funded a Muscular Dystrophy Cooperative Research Center. Researchers at the three centers are conducting studies on Duchenne, myotonic, and facioscapulohumeral muscular dystrophy, and investigating therapeutic approaches including stem cell and gene therapy. In a novel public-private collaboration, the Muscular Dystrophy Association agreed to commit additional funds to enhance activities at each of the three Centers funded. In FY 2004, NIAMS, NINDS, and NICHD re-issued the solicitation for cooperative research centers - now known as Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers, and expect to fund two to three additional meritorious centers in FY 2005.

Workshop on the Burden of Muscle Diseases

In follow-up to Congressional language, NIAMS, and the NINDS, NICHD and the Centers for Disease Control and Prevention, are actively planning a workshop on the burden of muscle diseases that will take place in January 2005. The purpose of the workshop is to identify existing data on the costs and scope of muscle diseases, with a focus on the muscular dystrophies, and to recommend strategies for developing new information sources.

Skin Biology and Skin Diseases

There are thousands of skin diseases catalogued to date, and most of them are clinically challenging for patients as well as their health care providers, while some can be devastating and even fatal. Researchers supported by the NIAMS have made great progress in our understanding of basic skin biology as well as understanding the bases for skin diseases.

Identification of Genes Associated with Psoriasis

A team of researchers funded by the NIAMS identified 2 genes on chromosome 17 which are associated with psoriasis. The region between these two genes acts as a binding site for the protein runx1, which normally serves to regulate genes involved in immune reactions. The researchers found that when this region is altered, susceptibility to psoriasis occurs. This defective regulation may cause an increased activation of T cells, a type of white blood cell that normally helps protect the body against infection and disease. Such activation triggers inflammation and rapid turnover of skin cells in people with psoriasis. It is also possible that the defective regulation could be affecting other cell types in the skin.

New Animal Models of Alopecia Areata

Alopecia areata is a common skin disease that results in intermittent patchy hair loss in the mildest cases to complete loss of all scalp hair. In the past, studies of alopecia areata have been hampered by the lack of a good animal model. Recently investigators have identified a mouse model that spontaneously develops an adult onset form of alopecia areata. This new model has allowed genetic susceptibility studies to be undertaken, and two new regions on chromosomes 8 and 15 were identified. Previous studies of these genes found that one of them corresponded to a human gene involved in autoimmunity, underscoring the autoimmune basis that alopecia areata is thought to have. These studies show that the genetic basis of alopecia areata is not confined solely to the genes involved in autoimmunity, and underscore the necessity of doing wide genomic searches for genes associated with this disease. The availability of this new animal model will allow better identification of the genetic basis of alopecia areata as well as provide a basis for testing potential interventions.

The Genetic and Molecular Basis of Keloids

Keloids are an abnormal form of scarring that disproportionately affects African Americans. These scars can be so large as to be not only unsightly but also may interfere with function. They tend to occur on the upper half of the body particularly on the head, neck, chest, and back which are particularly unfortunate sites with regard to social interaction as well as interference with bodily functions. In addition to being more prevalent and severe in African Americans they have a familial occurrence in all racial groups. In a recent advance, investigators used a technique of looking at all of the genes in humans to look for the particular genes or location of the genes that induce susceptibility to keloids. Using African American and Japanese families, this group was able to demonstrate a statistically significant location for the susceptibility to keloids on chromosome 2 in the Japanese family and on chromosome 7 in the African American family. It is not surprising that more than a single gene or gene position was identified given the heterogeneous nature of this disease.

Other investigators studied the physiologic basis for keloid formation, and they were able to determine that a blood vessel growth factor was likely to be associated with keloid formation. They were also able to determine that this particular blood vessel growth factor was abnormally present in keloids and, surprisingly, this was being produced by the overlying outer layer of skin, the epidermis, rather than by the dermis, the deeper layer of skin in which the abnormal scar was actually growing. This raises the interesting potential of being able to suppress keloid formation by topical application of an inhibitor of this molecule.

Predicting the Outcome in Chronic Wound Healing of the Skin

Chronic wounds in the skin are a major public health problem in the United States and one that is increasing as the population ages. Venous lower leg ulcers, diabetic foot ulcers and decubitus ulcers are major areas of concern and cost. Among the difficulties in dealing with these chronic wounds is trying to predict which wounds will be more difficult to heal and, therefore, should be treated with the advanced and often expensive procedures early, and which other markers of eventual healing can be substituted for complete closure of the wound in doing studies of new interventions. NIAMS-supported researchers recently designed a study based on existing datasets of over 20,000 individuals with venous leg ulcers to try to determine whether any of several potential prognostic factors correlated best with eventual closure of the ulcer. Other researchers focused on one of the most promising new avenues in the treatment of chronic skin wounds -- the use of a variety of bioengineered skin substitutes. They designed a classification system of both diabetic and venous ulcers that was applied in the evaluation of the healing following the use of a bioengineered skin. The scoring system successfully predicted which wounds would eventually heal completely and which would not. Applying a system like this, once validated, should allow the FDA to accept shorter duration trials with an end point other than complete wound closure which will greatly reduce the cost of such clinical trials.

Information Dissemination

Information dissemination is a crucial dimension of the NIAMS mandate. If Institute-supported researchers have powerful research results but they are not disseminated to patients and health care providers, these results are of limited value. Institute staff work with voluntary and professional groups across our broad mandate to ensure that patients and health care providers have the latest research-based information. We also work closely with these groups to ensure that we are not duplicating efforts.

The NIAMS is currently developing several unique information tools, including: a CD-ROM for health care professionals on pediatric rheumatic diseases (in partnership with the Arthritis Foundation); a middle school science curriculum about musculoskeletal and skin health (in partnership with the NIH Office of Science Education); and NIH Senior Health web site components on osteoporosis and Paget's disease of bone (with the NIA to complement an arthritis unit we created that is already operational).

NIAMS information dissemination efforts provide outreach in other ways as well: the Institute is working with the Health Resources and Services Administration (HRSA) to distribute NIAMS information packages to hundreds of HRSA's community health centers around the country, and we are exploring a similar distribution to the Indian Health Service's clinics. The NIAMS continues its community-based research initiative called the Health Partnership Program which is done in collaboration with Washington, DC, area community partners in an under-served part of the city, with the goal of helping us understand and address issues of health disparities in rheumatic diseases.

Conclusion

Bones, muscles, joints, and skin are central components of the human body. We now understand better how they develop and function normally, and how they are altered in disease. We now know much more about the roles of genetics, the environment, diet, and behavior in disease. Many chronic diseases affect women and minorities disproportionately, and we continue to actively pursue the causes of these gender and ethnic differences. Perhaps most noteworthy, we are making significant progress in our efforts to prevent disease in the first place. The NIAMS supports scientists who are making significant inroads in developing strategies for chronic disease prevention, and, as people are living longer lives, they are seeking strategies to maximize their quality of life and minimize the impact of the many chronic diseases that can compromise that quality of life. The research supported by the NIAMS demonstrates that medical research has made a genuine difference in the lives of all Americans.

Budget Policy

The Fiscal Year 2006 budget request for the NIAMS is $513,063,000, an increase of $1,906,000 and 0.4 percent over the FY 2005 Appropriation. Also included in the FY 2006 request, is NIAMS' support for the trans-NIH Roadmap initiatives, estimated at 0.89% of the FY 2006 budget request. This Roadmap funding is distributed through the mechanisms of support, consistent with the anticipated funding for the Roadmap initiatives. A full description of this trans-NIH program may be found in the NIH Overview.

A five year history of FTEs and Funding Levels for NIAMS is shown in the graphs below.

FTEs by Fiscal Year. In 2002, 245 FTEs. In 2003, 250 FTEs. In 2004, 220 FTEs. In 2005, 220 FTEs. In 2006, 220 FTEs
Funding Levels by Fiscal Year. In 2002, $447.8 million. In 2003, $486.6 million. In 2004, $500.9 million. In 2005, $511.2 million. In 2006, $513.1 million

NIH's highest priority is the funding of medical research through research project grants (RPGs). Support for RPGs allows NIH to sustain the scientific momentum of investigator-initiated research while pursuing new research opportunities. We estimate that the average cost of competing RPGs will be $298,400 in FY 2006. While no inflationary increases are provided for direct, recurring costs in noncompeting RPGs, where the NIAMS has committed to a programmatic increase in an award, such increases will be provided.

Advancement in medical research is dependent on attracting, training, and retaining the best and the brightest individuals to pursue careers in biomedical and behavioral research. In the FY 2006 request, most stipend levels for individuals supported by the Ruth L. Kirschstein National Research Service Awards are maintained at the FY 2005 levels. To help prevent the potential attrition of our next generation of highly trained post-doctoral trainees, stipend levels for post-docs with 1-2 years of experience are increased by 4.0%. This will bring these stipends closer to the goal NIH established for post-doc stipends in March 2000. In addition, individual post-doctoral fellows will receive an increase of $500 in their institutional allowance for rising health benefit costs. The need for increased health benefits is particularly acute for these post-doctoral trainees, who, because of their age and stage of life are more likely to have family responsibilities. The increases in stipends and health insurance are financed within the FY 2006 request by reducing the number of Full-Time Training Positions, because the NIH believes that it is important to properly support and adequately compensate those who are participating in these training programs, so that the programs can continue to attract and retain the trainees most likely to pursue careers in biomedical, behavioral and clinical research.

The Fiscal Year 2006 request includes funding for 40 research centers, 176 other research grants, including 52 clinical career awards, and 65 R&D contracts. Intramural Research and Research Management and Support receive increases of 0.5 percent, the same as the NIH total increase.

The mechanism distribution by dollars and percent change are displayed below:

FY 2006 Budget Mechanism pie chart. Research management and support, $22.9 million. Intramural research, $51.5 million. R and D contracts, $24.4 million. Research training, $15.5 million. Other research, $19.8 million. Research centers, $43.3 million. Research project grants, $335.3 million.
Bar chart showing FY 2006 Estimate Percent Change from FY 2005 by Mechanism. Research management and support, 0.3 percent. Intramural research, 1.3 percent. R and D contracts, 2.2 percent. Research training, minus 0.4 percent. Other research, 1.2 percent. Research centers, 3.8 percent. Research project grants, minus 0.3 percent.