Significant Items in Senate Appropriations Committee Report
FY 2004 Budget

February 2003 (historical)

The following section represents FY 2003 Congressional requirements for reports and significant items derived from Senate Report 107-216. These actions discussed below are contingent on inclusion of similar language and funding in the final FY 2003 appropriations and related reports. Additional items may be transmitted at a later date as a result of the final Conference report.

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Duchenne Muscular Dystrophy - The Committee urges NIAMS to intensify its research into the muscular dystrophies, and to continue working closely with the NINDS to identify collaborative opportunities to advance basic, clinical, and translational research into treatment for Duchenne muscular dystrophy. In addition, the Committee encourages NIAMS to coordinate with the NINDS and the Center for Disease Control and Prevention to develop strategic research priorities for basic and applied research in the Duchenne and Becker muscular dystrophies. (p. 128)

Action taken or to be taken

The NIAMS is committed to stimulating and supporting research to enhance our understanding of the causes of, and to develop potential treatments for, the various muscular dystrophies, including the Duchenne and Becker forms of this disease. Duchenne muscular dystrophy (DMD), and the related but less severe Becker form, are genetic, muscle-wasting disorders that are caused by mutations in the gene that codes for the protein dystrophin. The NIAMS is working collaboratively with the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Child Health and Human Development (NICHD) to develop major initiatives in this area, including new solicitations for muscular dystrophy cooperative research centers, and for training of basic and clinical scientists to study these diseases. New efforts funded as a result of these initiatives will complement on-going support for muscular dystrophy projects, which includes several studies designed to learn more about the progression of these diseases and ways to treat affected patients. To underscore the importance of work in this area, the NIH recently established a Muscular Dystrophy Research Task Force to ensure that we pursue all promising opportunities for research and training. We are also coordinating with colleagues at the Centers for Disease Control and Prevention, to identify potential collaborations as they support epidemiologic and surveillance projects in this field.

Scientists supported by the NIAMS have reported a number of recent advances in the muscular dystrophies. These include work done in mouse models of the disease to isolate special muscle-generating stem cells that can improve muscle regeneration, which were then used to deliver the missing protein dystrophin, and efforts to correct functional abnormalities of dystrophic muscle by using an adenoviral vector to deliver the protein dystrophin. Within the Institute's intramural research program, researchers have recently reported progress in understanding how a biochemical switch directs muscle building - insights from this work may lead to new approaches to correct problems that occur during embryonic muscle development. This research may also lead to methods to induce muscle growth, regeneration, and repair in adults. These and other discoveries give hope to patients, families, and caregivers who are directly affected by these diseases, and point researchers to fruitful areas for further study. Finally, the NIAMS is committed to developing and disseminating science-based health information on the muscular dystrophies. To this end, the Institute is planning to develop a publication describing challenges and opportunities in muscular dystrophy research, aimed at affected patients, practitioners, and the lay public.

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Gender Differences in Musculoskeletal Biology - Recent scientific advances have begun to make it possible to understand underlying gender-dependent differences that contribute to differences in disease incidence and severity between males and females. Osteoarthritis, rheumatoid arthritis, and osteoporosis are expressed to a greater extent in females. The Committee encourages NIAMS to work to identify the extent of these gender differences in musculoskeletal disorders and develop a plan for addressing the questions that require further research. (p. 128)

Action taken or to be taken

Many of the diseases within the research mission of the NIAMS have a disparate impact on women, and the Institute is committed to uncovering the bases of these gender disparities and developing effective strategies to treat and prevent them. The Institute currently funds several research centers that have a particular focus on diseases such as osteoarthritis, rheumatoid arthritis (RA), and osteoporosis. These centers foster interactions across a range of scientific disciplines, and facilitate the translation of basic research advances into clinical applications that benefit patients. In addition, the Institute has launched the Osteoarthritis Initiative, a novel public-private partnership to bring together new resources to help find biological and structural markers (biomarkers) for the progression of this degenerative joint disease, which affects millions of women.

To stimulate additional work on autoimmune diseases, such as RA, which affect many more women than men, the NIAMS participated in a request for applications on "Sex-Based Differences in the Immune Response," in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Neurological Disorders and Stroke, the NIH Office of Research on Women's Health (ORWH), and the National Multiple Sclerosis Society. This solicitation was designed to stimulate research on sex-based differences in immune responses that may be important in autoimmune diseases, and that could point the way to new treatment approaches. Related projects, funded in partnership with the NIAID, include work in mouse models to determine the relationship between viral immunity and lupus, another autoimmune disease, and efforts to explain the role of sex hormones in regulating the immune system. The Institute is also supporting efforts to develop biomarkers for RA and lupus which can be used in clinical settings to define disease subsets, and to follow the progression of these disorders. The NIAMS has also been an active member of the NIH's Autoimmune Diseases Coordinating Committee, which has recently developed a comprehensive research plan to guide future efforts in this area. Within the Institute's intramural program, a branch has been established to address the cellular and molecular basis of autoimmunity. A number of investigations are underway to study specific aspects of immune cell function as they relate to the development of autoimmune diseases.

In the area of osteoporosis, the NIAMS, in collaboration with the National Institute on Aging (NIA), supports a large study of osteoporosis and other age-related diseases in men, called Mr. OS. This project complements an ongoing study of osteoporotic fractures in women that has been supported by the Institute for over a decade. The Mr. OS effort will facilitate gender comparisons and address the issue of why osteoporotic fractures are more common in women. In addition, NIAMS joined with the NIA to support preliminary work in mice on an estrogen-like drug called estren that prevents bone loss without undesirable side effects. The Institute is also committed to stimulating research on how the biology of menopause contributes to health problems such as osteoporosis. In this regard, the NIAMS is participating in a program announcement on "Biology of the Menopausal Process and Associated Health Conditions During and After Menopause," along with NIA, NICHD, and the National Institute of Diabetes and Digestive and Kidney Diseases.

In other efforts, the Institute, in collaboration with the NICHD and the ORWH, recently released a program announcement on "Women's Health in Sports and Exercise" to stimulate a wide range of basic, translational, and patient-oriented clinical studies in this area. This solicitation follows up on a workshop that the Institute sponsored with the American Academy of Orthopaedic Surgeons to assess the current state of the science in this field, and to identify opportunities for further research. Projects which are funded through this announcement are expected to improve our basic knowledge of sports injuries in women, and help explain why female athletes are more susceptible to certain types of injuries. In addition, translational studies will aid the development of optimal prevention, rehabilitation, and training strategies. Finally, the NIAMS is funding a new specialized center of research to study sex differences in pain sensitivity, in collaboration with the ORWH. A particular focus of this center will be to explore the neural basis of temporomandibular joint pain, with a special emphasis on sex-related hypotheses for persistent, orofacial pain of deep tissue origin.

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Marfan Syndrome - Marfan Syndrome is a life-threatening genetic disorder affecting several organ systems including musculoskeletal, cardiovascular and ophthalmologic systems. To further boost research in this area, the Committee encourages NIAMS to consider all available mechanisms of funding for research on Marfan Syndrome. The Committee commends NIAMS for taking the lead role in the vital support of research on heritable disorders of connective tissues, which include Marfan syndrome. The Committee is pleased to note that NIAMS has issued a Request for Applications for heritable disorders of connective tissue. (p. 128)

Action taken or to be taken

Marfan syndrome is a heritable condition that affects the connective tissue. Individuals with Marfan syndrome tend to have excessively long bones and are thin. Other manifestations include skeletal malformations, abnormal position of the lens of the eye, and enlargement at the beginning part of the aorta, the major vessel carrying blood away from the heart. If left untreated, an enlarged aorta can lead to hemorrhage and even death. This disorder results from mutations in the gene that makes fibrillin-1, a major component of elastic fibers surrounding blood vessels.

The NIAMS has a long-standing interest in research on heritable disorders of connective tissue such as Marfan syndrome. In followup to the Third Workshop on Heritable Disorders of Connective Tissue, held in the fall of 2000, the Institute issued a request for applications for basic and clinical research on these diseases, in conjunction with the National Heart, Lung, and Blood Institute. In the fall of 2002, NIAMS announced the funding of eight new projects in response to this solicitation, including several that have important implications for Marfan syndrome. These new studies complement ongoing research supported by the Institute, which includes efforts to enhance our understanding of the cell biology of fibrillin and how defects in this system lead to disease, and work to boost our knowledge of the role of various tissue components in cartilage and bone development. Furthermore, the Institute is committed to developing and disseminating science-based health information for patients, families, and care givers affected by these conditions. To this end, NIAMS published a "Questions and Answers" booklet on Marfan syndrome, as well as a booklet on heritable disorders of connective tissue, which includes information on Marfan syndrome.

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Metabolic Bone Diseases - The Committee urges NIAMS to enhance its research into all metabolic bone diseases, to support research that applies new developments in genomics and proteomics to osteoporosis and related bone diseases, and to conduct large-scale clinical trials to determine whether agents that prevent bone loss reduce fracture risk in women with low bone mass. (p. 128)

Action taken or to be taken

The NIAMS leads the Federal research effort on osteoporosis and related bone diseases, and supports science ranging from very basic studies to clinical and translational projects, as well as early intervention and prevention efforts. Significant advances in the prevention and treatment of osteoporosis are available today as a direct result of research focused on determining the causes and consequences of bone loss at cellular and tissue levels, assessing risk factors, developing strategies to maintain and even enhance bone density, and exploring the roles of factors such as hormones, calcium, vitamin D, drugs, and exercise on bone mass. Currently, the Institute is working with colleagues in the Office of the Surgeon General to develop a report on osteoporosis and bone health. The report, which is slated for publication in the summer of 2004, will cover a range of topics including the burden of bone diseases; the state of the art in diagnosis, treatment, and prevention; and how to promote effective prevention strategies for better bone health. In other efforts to promote bone health, the NIAMS has published a guide for parents, "Kids and Their Bones." This new booklet underscores the importance of adopting healthy nutritional and lifestyle habits in childhood in order to reduce the risk of osteoporosis and fractures later in life.

For a number of years, the Institute has supported the Women's Health Initiative (WHI), a large-scale clinical trial of the effects of hormone therapy and calcium and vitamin D supplementation in postmenopausal women. Although results from the WHI have confirmed that estrogen and progestin reduce the risk of osteoporotic fractures in older women, other risks associated with this hormone therapy outweigh the bone health benefits. As a result, other therapies need to be explored to help women maintain a healthy skeleton as they age. Several important studies employing novel approaches are underway with support from the NIAMS, including projects focused on nitric oxide; phytoestrogens; and biophysical stimulation for osteoporosis. In addition, the NIAMS is supporting studies of the mechanisms of action of estrogen, which could lead to the development of estrogen-like drugs that protect bone without having undesirable side effects. The Institute also continues to fund clinical studies of combination therapies for osteoporosis, including low-dose hormone therapy and alendronate, and parathyroid hormone and alendronate. Furthermore, the Institute is developing an initiative to stimulate research using comprehensive gene expression assessment strategies to better understand the biology of musculoskeletal tissues and skin. Specifically, this effort will encourage NIAMS scientists to take advantage of new gene expression technologies that could reveal the overall patterns of differences between normal and pathological conditions of the musculoskeletal and skin systems. These, in turn, could point the way to new causal factors for disease, as well as potential therapeutic targets.

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Osteogenesis Imperfecta - The Committee encourages the Institute to pursue new osteogenesis imperfecta (OI) research opportunities arising out of the 2002 scientific workshop on OI, including life-threatening respiratory and cardiovascular problems related to osteogenesis imperfecta. (p. 128)

Action taken or to be taken

Osteogenesis imperfecta (OI) is a genetic disorder characterized by brittle bones that result in frequent fractures from little or no trauma. The NIH Osteoporosis & Related Bone Diseases~ National Resource Center estimates that OI affects 20,000 to 50,000 adults, children, and infants in the United States. Most often, the underlying cause is a defect in the gene that regulates the production of collagen, which is essential for the normal structure of bone. In OI, a person has either less collagen than normal, or a poorer quality of collagen than normal, leading to weak bones that fracture easily. The respiratory and cardiovascular consequences of OI are the result of spinal deformity and fractures. Although surgical procedures may alleviate the respiratory and cardiovascular problems to some degree, the focus of research continues to be on the fundamental skeletal pathology.

In the fall of 2000, the NIH held the Third Workshop on Heritable Disorders of Connective Tissue. In follow-up to that workshop, the NIAMS, along with the National Heart, Lung, and Blood Institute (NHLBI), issued a request for applications (RFA) entitled "Research on Heritable Disorders of Connective Tissue." This RFA was designed to stimulate research to better understand the disease progression of heritable disorders of connective tissue, such as OI, and to develop innovative treatment strategies. In the fall of 2002, the NIAMS announced the funding of eight new projects in response to this solicitation, including several that may have implications for OI. These new projects will complement on-going work on OI, which includes a set of grants awarded in the fall of 2001 for research activities designed to increase our understanding of skeletal pathology in OI, and to lead to improved therapeutic approaches to the disease.

In other efforts, the Institute joined with the NHLBI to issue an RFA on "Bone Formation and Calcification in Cardiovascular Disease." This RFA encouraged research on the possible link between the hardening of blood vessels (vascular calcification), bone formation, and cardiovascular disease. Projects funded as a result of this solicitation are bringing together experts in vascular cell biology, bone cell biology, and heart disease research. These investigators are studying common mechanisms that control vascular and bone calcification, which could lead to the development of new therapeutic strategies. Other promising areas of research currently underway include cartilage biology and mechanisms of its destruction and repair, genetic mutations in heritable disorders of connective tissue, and mechanisms of new bone formation. Research involving the biology of fracture repair and opportunities to enhance fracture healing and bone regeneration through biological repair mechanisms is also being pursued. Other advances include progress toward gene therapy of genetic bone diseases such as OI.

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Scleroderma - The Committee is encouraged by the NIAMS's growing interest in scleroderma, a chronic and progressive disease that predominantly strikes young women. More research is critically needed to identify the genetic risk factors for scleroderma and to develop safe and effective treatments. The Committee encourages the NIAMS to collaborate with other Institutes, including NHLBI, NIDDK, and NIDCR, to generate more comprehensive research opportunities for scleroderma. (p. 128)

Action taken or to be taken

Scleroderma results from 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 the disease. In other forms, however, the problem goes much deeper, affecting blood vessels and internal organs, such as heart, lungs, and kidneys. In scleroderma, the immune system is thought to stimulate cells called fibroblasts to produce excess collagen. Currently, there is no treatment that controls or stops the underlying problem: the overproduction of collagen. Little is known about the cellular changes that cause the skin and organs to harden, and the disease may be difficult to diagnose. Because the disease can affect multiple organ systems, several NIH components, including NIAMS, NHLBI, NIDDK and NIDCR, have an interest in scleroderma research and in high-quality applications for studies that are relevant to their respective missions.

Understanding the early cellular and molecular changes that precede scleroderma is critical to developing effective treatments. In response to this need, in the fall of 2001, the NIAMS awarded ten new grants to support research into the causes of scleroderma and to bring us closer to finding treatments. Two of these awards were co-funded by the NIH Office of Research on Women's Health. For example, one study is investigating the molecular basis for the closing down of blood vessels, which is a leading cause of death in scleroderma. Other researchers are examining mouse models to uncover the processes that cause collagen to accumulate, and whether persistent bacterial infection of the skin or small blood vessels is a potential cause of scleroderma. The underlying mechanisms of the cell transfer that occurs between mother and child in scleroderma is also under investigation. New projects in this area include studies of blood cells from scleroderma patients and nonaffected individuals to determine their origin and role in the development of this disease, as well as investigations of immune cells known as T cells in the skin of women and children with scleroderma. With respect to innovative therapies, the effectiveness of ultraviolet phototherapy for the treatment of localized forms of scleroderma is being tested, and work is underway in mouse models to study the early inflammatory events of skin fibrosis. Other studies are looking at the effect of race and ethnicity on scleroderma. In addition, the NIAMS currently supports two specialized centers of research in scleroderma, as well as a multidisciplinary clinical research center focused on pediatric rheumatic diseases, such as juvenile scleroderma. Finally, behavioral scientists supported by the Institute have found that managing pain and depression may lead to improved functioning and quality of life for patients with scleroderma.

Approximately 80 percent of scleroderma patients will eventually develop some degree of lung involvement, with restrictive lung disease (interstitial pulmonary fibrosis) now being the leading cause of morbidity and mortality in scleroderma patients. In collaboration with the NIAMS, the National Heart, Lung, and Blood Institute (NHLBI) is currently supporting a multicenter, randomized clinical trial to determine the effectiveness of cyclophosphamide in slowing the progression of lung disease in patients with scleroderma. The NHLBI also supports a major program of basic and clinical research on the etiology and pathogenesis of interstitial pulmonary fibrosis, which is expected to be beneficial in understanding lung fibrosis associated with scleroderma. Furthermore, NIDDK contributes to the science of scleroderma by supporting a large program devoted to research aimed at understanding the basic mechanisms that control motility of the gastrointestinal tract, which is impaired in patients with this disease.

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Skeletal Repair - The Committee encourages NIAMS to explore the stimulation of skeletal repair by biophysical agents including mechanical strain, ultrasound, and electrical energy. This research would be valuable to interdisciplinary interests including trauma, aging, rehabilitation and exercise physiology, and tissue engineering. (p. 128)

Action taken or to be taken

The NIAMS has a broad interest in the many factors that influence skeletal repair, and the Institute supports several studies aimed at improving our understanding of this process. This includes projects looking at the cellular and molecular mechanisms involved in skeletal growth, development and repair; specific mechanisms that may contribute to osteoarthritis; and the role of angiogenesis (blood vessel development) in bone repair. The Institute is also funding several projects aimed at understanding how bone responds to mechanical strain, which results from normal activity and is essential for maintaining bone mass. One such project is a pilot trial of mechanical stimulation to reduce bone loss in elderly women. Understanding this response could lead to new ways to prevent bone loss during prolonged bed rest, and could also lead to novel approaches to restore bone either at specific sites, or throughout the skeleton.

In addition, investigators funded by the NIAMS have recently reported advances that have important implications for this field. Such findings include new insights into the biology and physics behind the use of electrical stimulation for difficult-to-heal fractures, and to augment spinal fusions (a surgical procedure to allow one spinal bone to unite with an adjacent one); and the identification of key genes and proteins that control bone and cartilage formation in normal development which, in turn, could lead to new molecular tools to restore bone lost to injury or surgery, or to reconstruct cartilage in joints. Finally, the NIAMS has joined with the Canadian Institutes of Health Research to fund a three-year, multicenter study to determine the best way to repair the most common long bone fracture in the human body. The effort will compare different approaches to surgery involving fractures of the tibia (the larger of the two lower leg bones). Outcome measures to be analyzed include whether additional surgery is required to promote fracture healing; how soon patients return to work following surgery; and general health status and quality of life of participating patients.

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Temporomandibular Joint Disorders (TMJ) - The Institute is urged to initiate research on the unique features of the temporomandibular joint as well as explore to what extent temporomandibular diseases and disorders share common pathogenic mechanism with osteoarthritis in other joints and musculoskeletal pain. The recommendations from the recent TMJ Association meeting on joint and muscle dysfunction of the TMJ, which NIAMS co-sponsored, can serve as guidance for the NIAMS TMJ research agenda. (p. 129)

Action taken or to be taken

In the spring of 2002, the Institute helped to support a major meeting on joint and muscle dysfunction of the TMJ, in conjunction with the TMJ Association and the National Institute of Dental and Craniofacial Research (NIDCR). The recommendations which emerged from this meeting - which cover a number of scientific areas such as immunology, genetics, clinical issues, and deep tissue pain - will help shape the development of future initiatives in this area. In the fall of 2002, the NIAMS co-sponsored a request for applications, together with colleagues at the NIDCR and the NIH Office of Research on Women's Health (ORWH), to solicit cross-disciplinary applications on the pathobiology of the TMJ. Specifically, the Institute is encouraging ancillary projects to existing clinical studies of patients with adult and juvenile rheumatoid arthritis to explore TMJ involvement in these diseases. We anticipate that projects funded through this solicitation will focus on the evaluation of prevalence and clinical presentation of TMJ involvement in these disorders; the development of surrogate markers of disease activity; the identification of genetic markers; and the study of therapeutic effects. In addition, the NIAMS has launched the Osteoarthritis Initiative, a novel public-private partnership to bring together new resources to help find biological and structural markers (biomarkers) for the progression of this common, degenerative joint disease. One area of research within this initiative is to study the link between osteoarthritis and a history of orofacial pain. Finally, the Institute is funding a new specialized center of research to study sex differences in pain sensitivity, in collaboration with the ORWH. A particular focus of this center will be to explore the neural basis of TMJ pain, with a special emphasis on sex-related hypotheses for persistent, orofacial pain of deep tissue origin.

Tissue Reengineering - There is growing interest in the possibility that tissue engineering will provide a biological solution to the critical clinical need for organs and tissues. The Committee encourages NIAMS to consider holding a workshop to help educate clinicians, who can apply the advances to patients, about this new field. (p. 129)

Action taken or to be taken

The NIAMS has actively fostered interdisciplinary research that brings together biological and physical sciences, such as physics, engineering and mathematics. For example, the Institute supports biomaterials research that focuses on joint replacement, particularly extending survival of artificial joints. This ranges from basic research on the nature of the body's cellular response to implants, to surveys of long-term clinical results of joint replacements. We also support work to develop bioengineered skin that can be used to promote wound healing in patients with chronic, diabetic leg ulcers. The Institute is currently participating in program announcements to encourage additional research on orthopaedic implant wear, and functional tissue engineering of musculoskeletal tissue. We have also been an active member of the NIH's Bioengineering Research Partnerships Initiative, which seeks to support multidisciplinary projects that bring together bioengineering expertise with basic and clinical science, as well as the agency's Bioengineering Nanotechnology Initiative. In the Institute's intramural research program, efforts are underway to develop a tissue engineering research program focused on osteoarthritis, the most common form of arthritis.