Significant Items in House, Senate, and Conference Appropriations Committee Reports
FY 2007 Budget

February 2006 (historical)

FY 2006 House Appropriations Committee Report Language (H. Rpt. 109-143)

Item

Scleroderma - The Committee is encouraged by NIAMS's continued interest in scleroderma, a chronic and progressive disease that predominantly strikes women. Scleroderma is disfiguring and can be life-threatening, and effective treatments are lacking. The Committee encourages NIAMS to continue to collaborate with other institutes, including NHLBI, NIAID, NIDDK, and NIDCR, and through the NIH Autoimmune Coordinating Committee to generate additional research opportunities for scleroderma that may assist to identify genetic risk factors and the development of safe and effective treatments. (p. 87)

Action taken or to be taken

Scleroderma is a symptom of a group of diseases that involve the abnormal growth of connective tissue which supports the skin and internal organs. In some forms of scleroderma, hard, tight skin is the extent of this abnormal process. In other forms, however, the problem goes much deeper, affecting blood vessels and internal organs, such as the heart, lungs, and kidneys. NIAMS will continue to seek collaborations across NIH to promote and advance all areas of scleroderma research. In particular, NIAMS will continue to be an active member of the Autoimmune Diseases Coordinating Committee, working closely with committee members from NIAID, NHLBI, NIDDK, NIDCR, and other government organizations to better understand what causes the disease and to help develop more effective therapies.

Through molecular, cellular, and genetic research, NIAMS-supported researchers are closing in on the variety of factors involved in scleroderma. NIAMS is funding several studies seeking to identify the immune mechanisms that lead to scleroderma. For example, NIAMS-supported researchers have created a mouse model to examine the cross-talk between immune cells and fibroblasts, cells that form the connective tissues in the body. These researchers have been able to prevent skin hardening in the mouse model by using latency-associated peptide, a specific inhibitor of transforming growth factor beta, a molecule involved in the increased production of collagen - the major protein of the body's connective tissue. This research will add to the body of knowledge that can be used for the development of more effective diagnostic tools and immune-system-based therapies for scleroderma.

Other studies are investigating the genetic basis of scleroderma, seeking to identify the genes that contribute to the increased collagen production. NIAMS-supported researchers are also working to determine the roles of specific autoantibodies involved in the development and progression of different forms of scleroderma. Comparisons with autoantibodies found in lupus patients are informative in this study, and may lead to a deeper understanding of both diseases. Additionally, NIAMS-supported researchers are working to identify accurate biomarkers for the blood vessel damage associated with scleroderma. This study seeks ways of predicting pulmonary hypertension and other severe blood vessel consequences in patients with scleroderma.

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Burden of skin diseases - The Committee notes the release of the recent report, Burden of Skin Diseases, which supports evidence gathered at the September 2002 workshop on the burden of skin diseases sponsored by NIAMS. Based on these findings, the Committee encourages NIAMS to continue to strengthen the research portfolio on skin disease. The Committee also recommends that NIAMS consider potential partnerships with the skin disease research community to address the challenges outlined by the Burden of Skin Diseases findings. (p. 88)

Action taken or to be taken

NIAMS recognizes the burden of skin diseases report that was recently released by two leading professional organizations interested in skin research. As noted, many of the recommendations included in this report overlap with the results from the Workshop on the Burden of Skin Diseases, which was sponsored by NIAMS in September 2002. As an initial step in addressing the needs identified at this meeting, NIAMS-supported researchers are examining existing skin disease databases which could be used to address disease burden. Results from this study will guide next steps in identifying needs and developing future research endeavors, including potential partnerships between organizations, from both the public and private research sectors.

In other research efforts, NIAMS-supported researchers are working to identify the role of genes in the development of skin diseases in order to improve diagnostic, treatment and prevention options. For example, researchers are investigating genetic influence on the development of psoriasis, psoriatic arthritis, and atopic dermatitis, three diseases which can be both physically and psychologically devastating for patients. Researchers recently discovered similarities in genetic susceptibility for psoriasis and atopic dermatitis. As for psoriatic arthritis, the researchers found that the presence of modifier genes can indicate which individuals with psoriasis are also at risk for psoriatic arthritis. Additionally, other NIAMS-supported researchers working at the molecular level have developed a mouse model of psoriasis to examine the underlying mechanisms of disease, including genetics, and to explore novel treatment options. Taken together, these studies provide important information on what causes psoriasis, who gets it, and how it can be treated.

Other NIAMS-supported researchers have been studying familial vitiligo and its association with other autoimmune diseases in order to determine who is at risk for developing the disease. Using data from these families, the researchers were able to demonstrate not only the previously known association with autoimmune thyroid disease, pernicious anemia, Addison's disease and lupus but also an association with rheumatoid arthritis, psoriasis and adult onset insulin-dependent diabetes mellitus. Results from these studies could provide clues to disease development and progression enabling researchers to develop improved diagnostic, treatment and prevention options that would decrease the burden of disease and improve the quality of life of patients and their families.

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Psoriasis - Psoriasis is a chronic, immune-mediated disease that affects between 5.8 and 7.5 million Americans. The Committee recommends that NIAMS support additional research into this serious disease, both to identify the several genes believed to play a role in psoriasis pathogenesis, as well as to support additional clinical research on current and potential therapies for psoriasis and psoriatic arthritis. (p. 88)

Action taken or to be taken

Psoriasis is a chronic skin disease characterized by scaling and inflammation. Individuals with psoriasis may experience significant physical discomfort and some disability. People with moderate to severe psoriasis may feel self-conscious about their appearance and have a poor self-image that stems from fear of public rejection and psychosexual concerns. To this end, NIAMS funds a variety of research aimed at uncovering the cellular and molecular processes that contribute to the development of psoriasis and psoriatic arthritis, developing more effective treatments, and expanding our knowledge of genes that play a role in the development of these diseases in order to help increase the quality of life for patients.

Three recent NIAMS-funded studies are helping scientists and doctors to understand how psoriasis and psoriatic arthritis behaves at the molecular level and what role genes play in predisposing people toward these diseases. For example, NIAMS-supported researchers have found some similarities in genetic susceptibility for psoriasis and atopic dermatitis, another inflammatory skin disease. As for psoriatic arthritis, the researchers found that the presence of modifier genes can indicate which people with psoriasis are also at risk for psoriatic arthritis.

Other NIAMS-supported researchers have developed an animal model to demonstrate how the proliferation of T cells - cells that help to protect the body against infection and disease - is key to the formation of psoriatic lesions. The researchers also demonstrated the role of a molecule involved in the inflammation process, known as tumor necrosis factor alpha, in the development of psoriatic lesions and T cell growth. In another study, a team of scientists used psoriasis as a model disease to develop a way of identifying autoantigens (substances found naturally within the body that can trigger an immune response) for autoimmune diseases. The investigators found three autoantigens that were likely to be related to psoriasis and were associated with significant reactions in patients.

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Vitiligo treatment for children - Vitiligo is an environmental and genetic auto-immune disease of unknown origin which affects about three to six million Americans. Almost fifty percent develop the disease in childhood, with the median age of onset at four years of age. In its most severe forms, patients have milky white patches covering wide-spread areas of the body due to the loss of pigment in these areas. Especially for young children, the physical pain caused by severe burns from the harmful effects of sunlight and the emotional pain caused by people confusing vitiligo with an infectious disease diminish the quality of a patient's life. There are no FDA-approved treatments for children. The Committee encourages NIAMS to enhance research efforts through all appropriate mechanisms to identify the causes of this disease and develop pediatric treatment options for vitiligo. (p. 88)

Action taken or to be taken

Vitiligo is a disease in which white patches develop on the skin because of the loss of pigment production within the skin, and it is especially psychologically devastating in people of color. Children whose parents have the disorder are more likely to develop vitiligo; however, most people with vitiligo do not have a family history of the disorder. NIAMS-supported researchers are studying familial vitiligo in order to examine the genetic basis for the disease.

Statistically, vitiligo is associated with other autoimmune diseases. These other autoimmune diseases occur at greater frequency in relatives of patients with vitiligo even when those relatives do not have vitiligo themselves. Using data from a large cohort of patients and families, NIAMS-supported researchers are investigating the genes associated with the predisposition for vitiligo and other autoimmune diseases. The researchers have been able to demonstrate not only the previously known association with autoimmune thyroid disease, pernicious anemia, Addison's disease, and lupus but also association within families with rheumatoid arthritis, psoriasis and adult onset insulin-dependent diabetes mellitus. All of these diseases were found in greater frequency in the extended families of those with vitiligo.

The form of vitiligo that demonstrated this association was generalized vitiligo which has an earlier onset and is distinct from the other forms of the disease. The ability to recognize which subgroups of vitiligo may be associated with a higher incidence of autoimmune diseases in the family is an important finding that may allow for earlier diagnosis which can lead to better treatment options, particularly for younger patients. In addition, the further genetic analysis of patients and their families should provide clues to the underlying susceptibility to these diseases.

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Marfan Syndrome - The Committee commends NIAMS and its collaborative efforts with other institutes to provide support of research on Marfan syndrome, a life-threatening, progressive and degenerative genetic disorder which is characterized by aortic aneurysms, orthopedic disabilities and ocular manifestations which can result in blindness. Years of investment in basic research are ready to be translated to clinical studies of drug therapies with the potential of reversing many of the life-threatening and disabling symptoms of Marfan syndrome. These drug therapies may also prove to benefit people with other connective tissue disorders. The Committee encourages NIAMS to support clinical trials of new drug therapies through all available mechanisms, as appropriate. (p. 88)

Action taken or to be taken

Marfan syndrome is a heritable condition in which connective tissue is defective and does not function appropriately. It is caused by a mutation in the gene that determines the structure of fibrillin, a protein that is an important part of connective tissue. Because connective tissue is found throughout the body, the disease can affect many body systems, including the skeleton, eyes, heart and blood vessels, nervous system, skin, and lungs. Marfan syndrome affects men, women, and children, and has been found among people of all races and ethnic backgrounds.

NIAMS continues to support a multi-site translational research program in Marfan syndrome. The long-term goal of this program is to develop treatment strategies for individuals with Marfan syndrome and related disorders of connective tissue. Researchers are studying genetically engineered mouse models of Marfan syndrome to uncover the abnormal cellular activities that contribute to this disorder, and they will translate this new knowledge into more effective therapies. The program utilizes a comprehensive and multidisciplinary approach that integrates the scientific interest and expertise of four leading laboratories in this and related research fields.

As one example of the research being conducted by this consortium, researchers are using mouse models of Marfan syndrome in order to identify the molecular and cellular events responsible for the development and progression of aortal aneurysm, a common consequence of the disease. The goal of this study is to discover a basis for drug-based treatments of aneurysm in patients with Marfan syndrome. Another related study examining the molecular level is investigating the role of transforming growth factor-beta (TGF-beta, a signaling protein which regulates the activity of osteoblasts and osteoclasts) and its connection with the deficiency of fibrillin-1 that is characteristic of Marfan syndrome. If it can be determined that the lack of fibrillin-1 causes the overproduction of TGF-beta, resulting in some of the symptoms of Marfan syndrome, these studies may lead to new treatments based on blocking TGF-beta activity.

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Tuberous sclerosis complex (TSC) - TSC is a genetic disorder that triggers uncontrollable tumor growth in multiple organs of the body, including the skin. The Committee encourages NIAMS to support programs examining the molecular and cellular basis of dermatological lesions in TSC as well as the development of non-surgical treatments for skin manifestations. (p. 88)

Action taken or to be taken

NIAMS actively participates in the Trans-NIH Tuberous Sclerosis Coordinating Committee which is led by NINDS and includes representatives from other NIH components such as NCI, NIDDK, NIMH, NHLBI, NICHD, NIGMS and the NIH Office of Rare Diseases. Other participating organizations include the Department of Defense and the Tuberous Sclerosis Alliance. Members of the Coordinating Committee have reviewed and discussed the research portfolios of the participating organizations, including relevant ongoing clinical trials, in order to identify potential research partnerships and opportunities for targeted initiatives on tuberous sclerosis complex.

Recently, NINDS, NIDDK, NIMH, NIAMS, and NCI partnered with the Tuberous Sclerosis Alliance to release a program announcement focused specifically on tuberous sclerosis complex. The solicitation encouraged applications designed to broaden the base of knowledge related to the disease including the identification of new therapeutics. NIAMS encourages highly meritorious applications in mission-related research that is directly related to tuberous sclerosis complex including the development of non-surgical treatment options for the associated skin manifestations of the disease.

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Mucopolysaccharidosis (MPS) - The Committee encourages NIAMS to work collaboratively with NIDDK in an effort to achieve a greater understanding of the bone and joint lesions in MPS disorders. The committee supports NIAMS research addressing the underlying pathophysiology of bone and joint lesions, the gene mutations and substrates that are stored, and potential therapeutic approaches to treating these debilitating aspects of MPS and related disorders. (p. 88)

Action taken or to be taken

Mucopolysaccharidosis (MPS) is an inherited metabolic disorder that causes a variety of musculoskeletal problems including bone and joint irregularities resulting in short stature, stiff joints and curvatures of the spine. Progressive physical disability can result from these manifestations and neurological problems can also occur if nerves become compressed. Although treatments for these symptoms are available, there is currently no cure for the disease.

NIAMS is committed to advancing the understanding, diagnosis, treatment, and prevention of a broad range of bone and joint diseases. Currently, NIAMS supports a number of research programs designed to examine these diseases at the cellular and molecular levels and to utilize animal models in order to better understand the genetic aspects of disease. Advances in many of these areas could provide valuable insight into the development and progression of MPS. NIAMS would welcome highly meritorious applications relevant to our research mission that address the musculoskeletal issues associated with MPS. In order to facilitate this process and to identify appropriate research areas, NIAMS staff has meet with representatives of NIDDK and NINDS, as well as representatives of MPS patient advocacy groups, to consider opportunities for collaboration across the NIH.

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Osteogenesis Imperfecta - The Committee commends NIAMS for its support of promising gene-targeting stem cell research that could represent a potential cure for osteogenesis imperfecta and encourages continued support of this research. (p. 89)

Action taken or to be taken

Osteogenesis imperfecta (OI) is a genetic disorder characterized by bones that break easily, often from little or no apparent cause. OI is caused by a genetic defect that affects the body's production of collagen, the major protein of the body's connective tissue. In OI, a person has either less collagen or a poorer quality of collagen than normal, leading to weak bones that fracture easily.

The NIAMS supports several projects which focus on new and innovative treatment options for OI. NIAMS-funded scientists have developed a method of inactivating affected genes in cells from patients with severe forms of OI. These cells were shown to produce normal collagen and retain the ability to develop into mature bone-forming cells. Although this therapy will require further testing, it holds the promise of reducing the burden of disease. Advances like this bring scientists significantly closer to being able to repair genetic errors, not just for OI, but for many other diseases that are due to the activity of abnormal genes.

Other researchers are utilizing a mouse model of OI to evaluate the potential use of stem cells derived from bone marrow to facilitate the repair and regeneration of bone. The study seeks to test the idea that stem cells from normal donor mice, when infused into mice with OI, will contribute to the growth of healthy bone. This study may lead to the development of better treatments for genetic and non-genetic diseases of bone.

Additionally, NIAMS-supported scientists continue to investigate the molecular basis of OI and the use of new medications to treat it. For example, researchers are examining the chemical basis for the unique structure of collagen. This research will provide new insight into the interaction of collagen with other proteins, and could ultimately lead to the creation of collagen substitutes and collagen-based biomaterials with important therapeutic applications.

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Osteopetrosis - The Committee encourages NIAMS to increase support of research on models, methods, and modalities to increase bone formation and alter bone remodeling, and address the impact of aging, genetics, obesity, inactivity and exercise on bone at molecular, cellular, and tissue levels. NIAMS is encouraged to work with NICHD and NIDDK to strengthen research on the genetics and new treatments for the rare disorder osteopetrosis. (p. 89)

Action taken or to be taken

NIAMS supports a broad range of research on bone to better understand what causes the various forms of bone disease and to help develop more effective therapies. For example, researchers have been able to locate a gene that not only influences bone density in mice, but also provides new insight into how to preserve bone mass in humans. By locating relevant bone formation pathways, scientists may find additional clues to the prevention of bone diseases such as osteoporosis and resulting fractures.

NIAMS-supported researchers are also investigating a number of animal and cellular models of bone resorption, the process in which old bone is broken down and removed by specialized cells. The overall goal of these studies is to discover novel mechanisms in the control pathways that are relevant to bone health and disease. Identification of the molecular mechanisms of these pathways may reveal additional therapeutic targets that can be pursued to improve the clinical treatment of a variety of bone diseases.

Osteopetrosis is a group of congenital bone diseases that are characterized by an increase in skeletal mass resulting from inadequate bone breakdown. In osteopetrosis, the cells that break down bone (osteoclasts) usually are either fewer in number or are ineffective in breaking down bone, leading to dense but fragile bones. To date, the precise genetic control of osteoclast function remains inadequately understood. Improved treatment of bone disease awaits additional investigation into the complex control mechanisms that balance the formation and breakdown of bone. NIAMS supports a broad portfolio of bone research, including studies examining osteopeterosis, and would welcome opportunities to work with other components of the NIH with similar interests.

Recent studies have shown that certain mutations in the chloride channel cause a specific form of osteopetrosis, Type 2 autosomal dominant osteopetrosis or ADO2, but up to 1/3 of subjects with the same mutation remain unaffected carriers. This has led to the search for both environmental causes as well as other genes that modify the response to the mutation. New research involving eight multi-generational families with ADO2 has revealed that modifier genes may control the expression of the disease and determine its onset and severity. The identification of these modifier genes may provide further insight into the mechanism of this disease, but also may suggest new therapeutic targets for this and other metabolic bone diseases.

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Lupus - The Committee is aware that the discovery of lupus susceptibility genes may be a prerequisite to developing exciting new therapies for lupus and ultimately a way to prevent and cure the disease. Advanced new technologies make finding these genes less expensive and more feasible than ever before. The Committee is also aware that new consortia within the lupus community have been formed to facilitate genetic research. The Committee urges the Institute to strengthen its work in support of the collection of DNA, serum, genotyping and subject information from lupus patients, their family members and healthy unrelated controls so that the identification of the relevant genes can be explained. (p. 89)

Action taken or to be taken

For over 10 years, NIAMS has supported the Lupus Registry and Repository, a core facility dedicated to collecting and characterizing information from patients and their family members. The registry currently includes 624 pedigrees; 287 of these include multiple cases that are especially useful for genetic linkage analyses. DNA, plasma, and serum samples are available to researchers across the country and currently provide patient information to more than 28 other lupus-related projects. Additionally, NIAMS provides support for the Research Registry for Neonatal Lupus. This registry provides material for basic research on the causes of this disease, tracks important epidemiological data such as incidence, and facilitates family counseling. Data from both registries, as well as other ongoing genetics studies, will facilitate development of improved methods of diagnosis, prevention, and treatment.

NIAMS-supported researchers continue to make a significant impact on the landscape of lupus research. For example, a recent study supported by NIAMS and NIAID helps confirm the connection between lupus and the Epstein-Barr virus (EBV), particularly in those individuals with a genetic predisposition for the disease. Using information from the Department of Defense repository, researchers studied changes in the blood of people who later developed lupus, and were able to identify when people with lupus began to make the autoantibodies that damage target tissues. In people genetically predisposed to lupus, antibodies to a portion of the EBV protein cross-reacted with a piece of a protein in the body called Ro. This study provides new insight into how lupus begins, and it also has implications for treating or even preventing the disease.

Other researchers are examining new and existing treatment options for patients with lupus. For example, preliminary studies that were partly funded by the NIAMS show that the cancer medication rituximab may someday be effective against lupus. In a study of adults with lupus that was clinically active despite treatment, just one injection of rituximab eased symptoms for up to a year or more. While current lupus treatments work by suppressing the entire immune system, rituximab selectively targets the B cells - white blood cells that produce proteins called antibodies - that are at the root of the problem.

Additionally, women with lupus may experience the benefits of postmenopausal hormone therapy without an increased risk of severe disease flares, according to a major study funded by the NIAMS. In a 16-center study of menopausal women, those taking a standard regimen of hormone therapy had no statistically significant increased risk of severe flares compared to those taking a placebo. Women in the hormone therapy group were, however, about 20 percent more likely to have a mild-to-moderate flare. None of these mild-to-moderate flares resulted in the need for high-dose steroids or hospitalizations.

FY 2006 Senate Appropriations Committee Report Language (S. Rpt. 109-103)

Item

Bone Formation and Remodeling - The Committee encourages NIAMS to increase support of research on models, methods and modalities to increase bone formation and alter bone remodeling, and address the impact of aging, genetics, obesity, inactivity and exercise on bone at molecular, cellular, and tissue levels. NIAMS should work with NICHD and NIDDK to expand research on the genetics and new treatments for the rare disorder osteopetrosis. (p. 133)

Action taken or to be taken

Please refer to page NIAMS-34 of this document for NIAMS' response to this significant item regarding osteopetrosis.

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Burden of Skin Diseases - The Committee notes the release of the recent report, `Burden of Skin Diseases', which supports evidence gathered at the September 2002 workshop on the burden of skin diseases sponsored by NIAMS. Based on these findings, the Committee urges NIAMS to continue to expand the research portfolio on skin disease. The Committee also encourages that NIAMS consider potential partnerships with the skin disease research community to address the challenges outlined by the "Burden of Skin Diseases" findings. (p. 133)

Action taken or to be taken

Please refer to page NIAMS-29 of this document for NIAMS' response to this significant item regarding burden of skin diseases.

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Duchenne Muscular Dystrophy - The Committee continues to be concerned with the amount of time taken by NIAMS to complying with the MD Care Act. The Committee encourages the NIAMS to increase research for Duchenne Muscular Dystrophy. The Committee further requests that NIAMS coordinate with NINDS on timelines for translational research, a consensus conference and the strategic plan. (p. 133)

Action taken or to be taken

NIAMS, along with NINDS and NICHD, continues to actively work with both public and private organizations to respond to the major provisions of the MD-CARE Act. For example, NIAMS has been an integral component of the ongoing activities of the Muscular Dystrophy Coordinating Committee (MDCC). The MDCC has overseen the development of the Muscular Dystrophy Research and Education Plan for the NIH and the new Action Plan for the Muscular Dystrophies. The Action Plan, which refines the goals of the Research and Education Plan, has been designed to serve as a comprehensive document for the entire muscular dystrophy research and education community to use when developing future research activities related to the detection, diagnosis, treatment and prevention of all types of muscular dystrophy. The final draft of the Action Plan was presented to the MDCC on November 9, 2005, for review and comment. Once approved, the Action Plan will be available to the public.

As part of the MD-CARE Act, NIH was authorized to establish centers of excellence for muscular dystrophy. Currently, NIAMS provides support for two of the six existing Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers. Taken together, the six Centers provide expertise, infrastructure and resources focused on major questions about muscular dystrophy. NIH staff work closely with representatives from each Center to promote collaborations between Centers and to provide guidance and continued evaluation of research goals and progress.

NIAMS continues to develop its muscular dystrophy portfolio, including projects focused on translational research. Building on recent basic biology advances in the muscular dystrophies, NIAMS-supported researchers are exploring treatment options for degenerative muscle diseases including pharmacological, and gene- and cell-based therapies. NIAMS-supported researchers are working to identify and test potential drugs used to block the enzymes that cause muscle degeneration, and pharmacological methods to promote muscle growth. Additionally, NIAMS supports several other translational research projects aimed at developing and testing recombinant viruses engineered to be vehicles for the delivery of therapeutic genes that may block or reverse muscle degeneration. In collaboration with NINDS, the NIAMS will soon release a set of two program announcements to further advance NIH-supported translational research in the muscular dystrophies. Specifically, these initiatives will implement a broad-based translational research program of exploratory/developmental research projects and cooperative agreements with the goal of developing new and more effective treatments.

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Lupus - The Committee recognizes lupus is a serious, complex, debilitating chronic autoimmune disease that can cause inflammation and tissue damage to virtually any organ system in the body and impacts between 1.5 and 2 million individuals. This autoimmune disorder affects the skin, bones, joints, connective tissue and vital organs. The Committee is disappointed with the pace of research regarding lupus and strongly urges the Director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases to expand and intensify research and related activities with respect to lupus. (p. 133)

Action taken or to be taken

Please refer to pages NIAMS-35 of this document for NIAMS' response to this significant item regarding lupus.

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Marfan Syndrome - The Committee commends NIAMS and its collaborative efforts with other Institutes to provide vital research on Marfan syndrome, a life-threatening, progressive and degenerative genetic disorder that is characterized by aortic aneurysms, painful orthopedic issues, pulmonary issues and ocular manifestations. Years of basic research are ready to be translated into a clinical trial for a drug therapy that may potentially prevent and reverse many of the life-threatening aspects of this syndrome. In addition, it may help many of the disabling characteristics not only of Marfan syndrome but also of other connective tissue disorders. The Committee urges NIAMS to support this effort through all available mechanisms, as deemed appropriate. (p. 134)

Action taken or to be taken

Please refer to pages NIAMS-31 of this document for NIAMS' response to this significant item regarding Marfan syndrome.

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Mucopolysaccharidosis [MPS] - The Committee encourages the NIAMS to work collaboratively with NIDDK in an effort to achieve a greater understanding of the underlying pathophysiology of bone and joint lesions in MPS disorders, the gene mutations and substrates that are stored, and potential therapeutic approaches to treating these debilitating aspects of MPS and related disorders. (p. 134)

Action taken or to be taken

Please refer to page NIAMS-33 of this document for NIAMS' response to this significant item regarding mucopolysaccharidosis.

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Osteogenesis Imperfecta.--The Committee commends NIAMS for its support of the promising gene targeting stem cells research that represents a potential cure for osteogenesis imperfecta and encourages continued support of this research. (p. 134)

Action taken or to be taken

Please refer to pages NIAMS-34 of this document for NIAMS' response to this significant item regarding osteogenesis imperfecta.

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Osteoporosis - The Committee urges the study of genetics of osteoporosis including, studies to determine the causes of variation in peak bone mass and rates of bone loss and therapies to lower fracture risk in patients at high risk for osteoporotic fractures. (p. 134)

Action taken or to be taken

Osteoporosis is a disease characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased risk of fractures. Although scientists know that many genes influence bone mass and thus osteoporosis risk, identifying specific genes has been challenging - especially in humans, who are genetically diverse.

NIAMS supports several studies examining the genetic determinants of the material properties of bone including bone mineral density (BMD) and bone quality in both human and animal models. BMD is the most widely used measure in the assessment of osteoporosis and fracture risk and is very valuable clinically; however, there are some limitations to using BMD alone for either genetic studies or for the assessment of fracture risk. Cutting edge imaging, as well as biomarker research, is currently exploring other characteristics of bone that may inform studies of skeletal health and fracture risk. Discovery of the genes essential for optimal bone quality would offer tremendous insight into overall bone strength. These studies also have the potential to lead to new developments in the prevention and treatment of osteoporosis.

In recent studies, NIAMS-supported researchers have been able to locate a gene that not only influences bone density in mice, but also provides new insight into how to preserve bone mass in people. These researchers identified the gene, called alox15, while working with two strains of mice that have very different bone mineral densities. Variations in the gene account for a significant part of that difference. While scientists have known of the gene for some time, it was never recognized as important to the skeleton. The discovery of alox15's influence on bone mass suggests that previously unsuspected metabolic pathways could be important for skeletal health. By further studying this pathway, scientists may find additional clues to the prevention of osteoporosis and the resulting fractures.

In addition to the research previously mentioned, NIAMS recently sponsored the meeting, Bone Quality: What Is It and Can We Measure it?, in May 2005. This scientific meeting brought together leading scientists from around the world to identify needs and future directions in bone quality research; highlighted basic science, clinical, regulatory, and pharmaceutical perspectives. Participants assessed established and new methods for measuring bone fragility as well as how to facilitate their inclusion in clinical trials; and they discussed novel mechanisms to bring together research efforts on bone quality to move this research field forward. The NIAMS partnered with the American Society for Bone and Mineral Research, the French Institute of Health and Medical Research (INSERM), and the NIH National Institute of Biomedical Imaging and Bioengineering in sponsoring this meeting.

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Paget's Disease- The Committee urges NIAMS to study the role of genes and the underlying abnormal functioning of cells involved in bone breakdown in Paget's disease patients. Further research is needed on the role the bone microenvironment plays in the development of Paget's disease and the molecular processes involved. (p. 134)

Action taken or to be taken

Paget's disease is a chronic disorder that can result in enlarged and misshapen bones. The excessive breakdown and formation of bone tissue causes affected bone to weaken - resulting in bone pain, fractures, and arthritis in the joints near the affected bones. The underlying causes of Paget's disease are complex, and are still poorly understood. Likely contributing factors include chronic infection with certain viruses and inherited predisposition to develop the disease in some families. However, it is clear that a key feature of the disease is excessive numbers and activity of osteoclasts, the cells that are responsible for bone breakdown.

NIAMS supports an integrated multi-project program of research into the biological mechanisms underlying the development of Paget's disease. These efforts have shown that osteoclast precursors from people with Paget's disease are unusually sensitive to dihydroxyvitamin D3 (Vitamin D3). This form of the vitamin is normally present in the body and is important for a number of metabolic processes. The normal levels of Vitamin D3 that are present do not stimulate formation of osteoclast cells. However, when the cells from people with Paget's disease are exposed to the same levels of Vitamin D3, they readily form osteoclasts. In recent work, investigators have identified components of the molecular machinery responsible for this hyper-responsiveness to Vitamin D3 in individuals with the disease, one of which is a protein called the vitamin D receptor (VDR). VDR has been studied for many years and a number of drugs, called VDR antagonists, have been developed that block the action of VDR in cells. Investigators have now tested one of these VDR antagonists in cultures of bone marrow cells from people with Paget's disease. They found that the VDR antagonist effectively prevented the stimulation of osteoclast formation by Vitamin D3. This suggests that VDR antagonists could be useful in the treatment of Paget's disease.

Other NIAMS-supported investigators are seeking to identify the genetic basis of a disease in which myopathy (muscle damage) is associated with Paget's disease. This work may reveal previously unsuspected biochemical pathways that can contribute to the development of Paget's disease. Other NIAMS-supported researchers are employing a variety of molecular and cellular techniques, as well as transgenic animal models, to provide new insights into the mechanism of osteoclast formation. Improved understanding of the regulation of bone breakdown may provide novel targets for the development of pharmaceutical agents aimed at preventing bone destruction associated with bone disorders such as Paget's disease.

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Psoriasis - Ten to 30 percent of psoriasis patients develop psoriatic arthritis, a painful and potentially destructive joint disease. The Committee urges NIAMS to support additional genetic research to identify the genes responsible for psoriasis susceptibility, basic research to understand the mechanism of disease and clinical research to identify new safe and effective therapies for these diseases. (p. 134)

Action taken or to be taken

Please refer to page NIAMS-30 of this document for NIAMS' response to this significant item regarding psoriasis.

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Scleroderma - The Committee is encouraged by NIAMS's continued interest in scleroderma, a chronic and progressive disease that predominantly strikes women. Scleroderma is disfiguring and can be life-threatening, and effective treatments are lacking. The Committee encourages NIAMS to continue to collaborate with other Institutes, including NHLBI, NIAID, NIDDK, NIDCR, and through the NIH Autoimmune Coordinating Committee to generate additional research opportunities for scleroderma that may assist to identify genetic risk factors and the development of safe and effective treatments. (p. 134)

Action taken or to be taken

Please refer to pages NIAMS-28 of this document for NIAMS' response to this significant item regarding scleroderma.

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Tuberous Sclerosis Complex - Tuberous sclerosis complex, or TSC, is a genetic disorder that triggers uncontrollable tumor growth in multiple organs of the body, including the skin. The Committee is encouraged that NIAMS is participating in a Trans-NIH Tuberous Sclerosis Coordinating Committee, and strongly encourages NIAMS to continue to assist the clinical research community in the development of standardized protocols for skin assessment and the development of pilot clinical trials. (p. 135)

Action taken or to be taken

Please refer to page NIAMS-32 of this document for NIAMS' response to this significant item regarding tuberous sclerosis complex.