About Us

Congressional Justification Narrative
FY 2002

February 2001 (historical)

Authorizing Legislation: Section 301 of the Public Health Service Act, as amended. Reauthorizing legislation will be submitted.

Budget Authority:

  FY 2000 Actual FY 2001 Estimate FY 2002 Estimate Increase or Decrease
BA $349,299,000 $396,603,000 $443,565,000 $46,962,000
FTE 188 205 213 8

This document provides justification for the Fiscal Year 2002 activities of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), including HIV/AIDS activities. A more detailed description of NIH-wide Fiscal Year 2002 HIV/AIDS activities can be found in the NIH section entitled "Office of AIDS Research (OAR)."

Introduction

Improving daily life is the driving force for the research that we support and conduct at the NIAMS. Virtually every home in America is touched by diseases affecting bones, joints, muscles, and skin. We are committed to better understanding, diagnosis, treatment, and prevention of these diseases and disorders that are often chronic and disabling, many of which disproportionately affect women and minority populations.

The stories of progress and promise below illustrate well the fact that research across a broad spectrum is essential – for it is basic research at the laboratory bench that informs clinical research on patients at the bedside. The converse is equally true – we count on physician researchers at the bedside to stimulate basic studies that will ultimately yield information useful to patient care and disease prevention. We are indebted to the scientists around the country and on the NIH campus who have dedicated their lives and their talents to pursuing careers in research. They are the heroes who devote countless hours and great expertise to pursuing the research puzzles and challenges that characterize the chronic diseases of bones, joints, muscles, and skin. It is with pride and excitement that we report the research advances of the past few years, and the ongoing and new research initiatives that enhance strong research programs in areas of scientific opportunity.

Science Advances and New Research Activities

Health Disparities

Diseases within our research mandate affect people of all ages and ethnicities, but we know that groups such as African Americans, Hispanic Americans, American Indians and Alaskan Natives, and Asian Americans experience many of these diseases both in increased numbers and increased severity. Compared to the general population, the prevalence of systemic lupus erythematosus (lupus or SLE), an autoimmune disease that can range from a mild skin rash to major organ failure, is higher among African Americans and Hispanic Americans. These groups also experience more complications of lupus. African Americans also have higher rates of hip and knee osteoarthritis, a degenerative joint disease that causes pain and joint damage. Scleroderma, an autoimmune disease that causes hardening of the skin and can affect major organs, occurs with greater frequency in Choctaw American Indians. Asian American women experience rheumatoid arthritis at rates higher than the general population as well. In addition, African American people are also disproportionately affected by overgrowths of scar tissue (keloids) and by loss of pigmentation (vitiligo), both of which may be severely disfiguring.

We are committed to identifying the root causes of these differences and to addressing health disparities. The NIAMS supported a meeting on December 15-16, 2000, "Health Disparities in Arthritis and Musculoskeletal and Skin Diseases," co-sponsored by a number of other NIH components and several professional groups. The goals of this conference were to (1) review current knowledge about health disparities in arthritis and musculoskeletal and skin diseases and (2) promote new research opportunities and approaches to eliminating disparities in the incidence and course of these diseases in ethnic groups at increased risk. We will take the recommendations of the distinguished participants in this meeting and develop research initiatives to address and close the gap in health disparities.

Health Partnership Program
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The health of a nation depends on the health of its communities. Recognizing this, the NIAMS is launching the first phase of its Health Partnership Program – A NIAMS Diversity Outreach Initiative, a new program to address the health disparities in joints, muscles, bones and skin diseases that exist in minority communities. The initial phase of this Program has begun as a model community-based program in the African American community in the metropolitan Washington, D.C., area, with the focus on rheumatic diseases. Presently, the program concentrates on four key areas: (1) public health education, (2) patient care, (3) access to clinical investigations, and (4) recruitment to research careers. As a component of this partnership, plans are also underway for a new rheumatology clinic to be located in a centrally accessible area of Washington, D.C.

Recruitment to Research Careers.

Specific strategies are underway and planned to increase the number of underrepresented minority investigators in the biomedical research fields related to the diseases within our mandate. These include developing science education curricula as well as training and mentoring programs for students, teachers and researchers. In other efforts in this area, the Institute has recently issued a Request for Applications for planning grants for clinical research training in minority institutions. We teamed with other NIH components in this effort to stimulate the inclusion of high quality, multidisciplinary didactic training as part of the career development of clinical investigators (in medicine, dentistry, nursing, and pharmacy) being trained in minority institutions.

We have also invested heavily in studies of diseases that disproportionately affect minority populations, such as lupus, scleroderma, and vitiligo. Advances in our knowledge of these diseases follow.

Systemic Lupus Erythematosus (Lupus).

A person's ethnicity does influence his or her experience with lupus. Ethnicity includes race as well as cultural values and beliefs and practices, which in the United States are associated with a certain socioeconomic status. Ethnicity, in fact, may affect patients with lupus. This information comes from the study LUpus in MInorities: NAture versus Nurture (LUMINA), conducted by NIAMS-supported researchers. The study, which includes over 300 African American, Hispanic and Caucasian lupus patients aged 20 to 50 years, is designed to identify the relative contribution of genetic and socioeconomic factors on the course and outcome of lupus among these three ethnic groups. LUMINA researchers are investigating features such as socioeconomic-demographic characteristics (e.g., age, gender, marital status, income, health insurance); clinical attributes (e.g., disease onset and duration, clinical manifestations, treatments); behavioral-psychosocial factors (e.g., social support, abnormal illness-related behaviors, feelings of helplessness, acculturation [Hispanics only]); immunologic factors (e.g., autoantibodies); and genetic factors. To date, the LUMINA study reveals that ethnicity, more than several other factors, does make a significant impact on some aspects of the disease. Both African American and Hispanic lupus patients tend to develop lupus earlier in life, experience greater disease activity at the time of diagnosis (including kidney problems), and have more severe disease overall than Caucasian patients. Further, African American patients have a higher frequency of neurologic problems such as seizures, hemorrhage and stroke, while Hispanic patients experience cardiac disease more frequently. Although LUMINA results, to date, do not implicate genetic influences as commonly responsible for differences in the early course of disease among these ethnic groups, researchers believe there are relevant genetic factors to be identified. The NIAMS is also supporting several groups of investigators who are attempting to identify the complex genetic factors that contribute to lupus susceptibility.

In basic research on lupus, scientists have recently issued the first report describing the application of gene transfer technologies to experimental models of lupus. In this report, investigators describe the therapeutic application of intramuscular injection of DNA encoding a protein that blocks lupus onset in lupus prone mice. These results highlight the value of DNA transfer for the treatment of autoimmune diseases.

Scleroderma

Synthesis of collagen (a major protein component of the skin and connective tissue) and its accumulation are essential for normal tissue development and wound repair. However, excessive collagen deposition can lead to fibrotic (excess connective tissue) diseases such as scleroderma. In recent reports from NIAMS-funded studies, investigators have found that scleroderma cells are resistant to factors that can normally regulate collagen production. These results may suggest that, by targeting these factors, new therapeutics could be developed to restore a balanced collagen synthesis in scleroderma fibroblasts.

To build on the strong research base currently being supported in scleroderma and to pursue research needs, the NIAMS issued a Request for Applications to foster developmental and traditional research projects to advance our understanding of the causes of scleroderma and to promote the design, development and pilot testing of innovative therapeutic approaches. This solicitation for grants follows a workshop at which experts identified scientific opportunities to pursue. We hope to encourage new and established researchers to focus on the causes of scleroderma and to devise new and innovative treatments.

Vitiligo

A newly awarded grant from the NIAMS will attempt to map the locations of genes that put people at risk for vitiligo, a common, autoimmune, skin pigmentation disorder characterized by white patches of skin. Vitiligo is particularly significant in dark-skinned people. While most pigmentation disorders are not more common in any one racial or ethnic group, they are of greater societal, social and psychological importance in the more darkly pigmented races. The study aims to map the location of vitiligo susceptibility genes in families with four or more affected relatives. Pairs of siblings affected by the disease will also be studied. Finding the locations of these susceptibility genes should speed up the identification and characterization of the genes themselves.

Research in Children

We are understanding more and more that, in many ways, children are not small adults – diseases affect them differently and treatment responses often vary significantly in children. The NIAMS has undertaken a number of programs and activities focused on children to enhance our understanding of childhood diseases and to develop improved treatments for our younger generation.

NIH Pediatric Rheumatology Clinic

The NIAMS Intramural Research Program launched an exciting and promising research initiative in the fall of 2000 at the NIH research hospital – the new NIH Pediatric Rheumatology Clinic. The clinic offers diagnosis, evaluation, and treatments for children with arthritis and other rheumatic diseases. Pediatric rheumatic diseases include juvenile rheumatoid arthritis, lupus, scleroderma, dermatomyositis, familial fever syndromes, and other chronic diseases that affect joints, muscles, bones, and skin. The clinic will provide children with a place where they can be diagnosed and treated in a state-of-the-art facility, and researchers can learn much more about rheumatic diseases.

Treatment for Juvenile Rheumatoid Arthritis

Enbrel® (etanercept) has been shown to be a safe and effective drug in the treatment of children and teenagers with juvenile rheumatoid arthritis (JRA), according to recent clinical trial results from one of the NIAMS Multipurpose Arthritis and Musculoskeletal Diseases Centers and investigators in the Pediatric Rheumatology Collaborative Study Group. The success of this clinical trial is also the culmination of many years of basic research supported by the NIAMS and other NIH components. Enbrel® belongs to a new class of drug treatments called "biologic agents" that are designed to interfere with the specific biological process of a disease. Enbrel® acts as a "sponge" to absorb a tumor necrosis factor (TNF), a naturally occurring protein that causes inflammation. For those children given Enbrel® in this trial, all measures of arthritis impact — symptoms, joint abnormalities, ability to perform daily functions and laboratory tests — were dramatically improved, and the drug was well tolerated. These findings offer hope for children with juvenile rheumatoid arthritis, hope for their ability to live their lives as active children.

Osteoporosis and Children

When most of us hear the term osteoporosis, we think of elderly women whose bones are deteriorating. What we now understand is that osteoporosis may actually start in childhood. This means that we must widen our scope of study to include people of all ages in research on osteoporosis.

Research studies on young girls revealed that minor variations in a gene for the bone protein, collagen, can lead to lower bone density. Major mutations (changes) in the collagen gene can lead to very disordered bone as in osteogenesis imperfecta, a disease manifesting in early life with multiple fractures and growth abnormalities. If minor variations in the collagen gene are associated with differences in bone density, these effects should be manifest in childhood. Researchers studied over 100 prepubertal girls, measured the bone mineral density, and also assessed the bone size and the genetic makeup of the collagen gene in each girl. They found that girls with a particular type of collagen gene variant had almost 50 percent lower bone mineral density than girls with a different collagen gene variant. Thus, these minor variations in the gene for collagen protein, while not causing apparent disease, may define a high susceptibility group for osteoporosis later in life. Identifying and understanding genetic susceptibility to osteoporosis early in life may facilitate the targeting of interventions to those who will most profit from them.

Autoimmunity

Research has resulted in significant progress in our understanding of autoimmune diseases, but 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 on this is integral to the Institute. Diseases in this category include rheumatoid arthritis, systemic lupus erythematosus, 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. Expanded studies are needed to identify causative agents or components of the body involved in autoimmune disease.

Estrogen and Autoimmunity

It is well established that women are at increased risk for autoimmune diseases. Lupus, rheumatoid arthritis and multiple sclerosis, among others, are more common among women than men. In these diseases, the immune system function goes awry, and immune responses against the body's own tissues and organs develop. Scientists have long suspected that sex hormones such as estradiol, may be the culprit for the increased risk, but the mechanisms underlying this effect are unknown. Working with an animal model genetically manipulated to produce autoantibodies under the appropriate signals, NIAMS-funded researchers have studied the effects of the female hormone estradiol in the induction and improper regulation of immune responses directed against the body's own tissues. They explored the effects of estradiol in immune cells that produce autoantibodies (B cells), and noted that estradiol makes B cells more resistant to signals that turn them off. In genetically manipulated mice that are able to produce autoantibodies, administration of estradiol induced lupus-like disease. In contrast, estradiol had no effect on cells from normal mice. These studies provide important information on the role of sex hormones in autoimmunity. Understanding the interactions between key processes during the development of tolerance and autoimmunity and sex hormones will significantly improve our understanding of mechanisms of disease.

Genetic Factors in Rheumatoid Arthritis

Recent studies suggest that the expression of genes that regulate cell fate may be responsible, at least in part, for the activated inflammatory state of cells lining joints (synovial fibroblasts) and destruction of cartilage and bone in rheumatoid arthritis. Investigators studied the hypothesis that in rheumatoid arthritis, the synovial membrane is gradually re-populated by immature bone marrow cells that express embryonic growth factors. They discovered that rheumatoid arthritis synovial cells express eight of these factors. When cultured in the laboratory, the rheumatoid arthritis cells expressing the embryonic growth factors also produced inflammatory cytokines (substances involved in cell-to-cell communication). The expression of embryonic growth factors appears to precede the production of inflammatory cytokines, since introduction of genes encoding these products into normal fibroblasts induced the production of cytokines (interleukin 6, 8 and 15). These results indicate that intrinsic properties of the synovial cells, independent of the immune response, may contribute to local changes observed in joints of rheumatoid arthritis patients. These results offer an opportunity for the development of new therapies designed to modify the activities of synovial cells as a new target for intervention.

Inflammatory Myopathies

It has been thought that autoimmunity (immune responses against the body's own muscles, joints, skin, etc.) may actually arise as a consequence of an appropriate immune reaction to an infection. The "appropriate" reaction then becomes inappropriate when it spreads to normal tissues. One of the NIAMS intramural laboratories has been working to develop an animal model of one of the autoimmune diseases, myositis (inflammation of muscle), by making a genetic change in the surface of muscle cells. Although no outside infection was involved, the animals developed muscle damage and autoantibodies of a kind that are found only in myositis in humans. This establishes that the development of this kind of autoimmunity does not require any particular outside stimulus, but may arise as a programmed consequence of the body's response to certain kinds of alterations within the tissues.

Osteoporosis

Consensus Development Conference

The NIH sponsored a Consensus Development Conference on Osteoporosis Prevention, Diagnosis, and Therapy on March 27-29, 2000. Osteoporosis, once thought to be a natural part of aging among women, is no longer considered age or gender-dependent. It is largely preventable due to the remarkable progress in the scientific understanding of its causes, diagnosis, and treatment. The consensus development panel's statement addressed four key questions: (1) What is osteoporosis and what are its consequences? (2) How do risks vary among different segments of the population? (3) What factors are involved in building and maintaining skeletal health throughout life? and (4) What is the optimal evaluation and treatment of osteoporosis and fractures? The panel provided responses to these issues, as well as a number of recommendations for future research across the broad spectrum of studies on osteoporosis. The major conclusions were that: (1) osteoporosis can be a devastating disorder that often goes unrecognized; (2) risk for low bone density and risks for fractures overlap, but may not be identical; (3) adequate calcium and vitamin D intake and regular exercise as well as gonadal steroids contribute to high peak bone mass; and (4) assessment of bone mass and fracture risk and determination of who should be treated are optimal goals, since effective treatment and prevention for both osteoporosis and for fractures have been identified.

Osteoporosis Therapies Prevent Bone Cell Death

Bone resorption (by cells called osteoclasts) is a normal part of bone remodeling, in which old or damaged bone is replaced with new bone. New bone is formed by other cells, called osteoblasts. Net loss of bone, leading to osteoporosis, occurs when bone resorption exceeds bone formation. The use of drugs known as bisphosphonates, which inhibit bone resorption, has brought about a marked improvement in the clinical management of diseases that involve bone loss. However, recent findings suggest that bone loss is associated not only with excessive bone resorption but also with the death of bone-forming osteoblasts. Other bone cells, called osteocytes, which are derived from osteoblasts when the bone-forming cells become embedded in the bone, also die under conditions that lead to bone loss. This may be important because osteocytes seem to be the cells that sense mechanical loading, a requirement for a healthy skeleton. Now, researchers have revealed that bisphosphonates can prevent the death of osteoblasts and osteocytes. It is likely that this action accounts, in part, for the effectiveness of bisphosphonates in treating several different types of bone loss. In addition, if the mechanism by which bisphosphonates prevent cell death can be identified, it may be possible to exploit this effect to a greater degree, leading to therapies that actually increase bone mass.

Obese Mouse Reveals New Approach to Building Bone

A very surprising observation has been made by investigators studying genetically obese strains of mice. These mice are defective in the action of a chemical called leptin, which acts through the central nervous system to control food intake along with several other aspects of behavior and physiology. In the absence of leptin's normal action, the mice become very fat. Usually, high body weight results in high bone mass. However, these mice also have defects in the development of the sex organs and have high levels of a naturally occurring chemical called cortisol, conditions that usually cause bone loss. Surprisingly, the mice had very high bone mass. Further, the high bone mass was not due to the obesity, but instead to the absence of leptin function. It seems that leptin normally acts to suppress the bone-forming activity of osteoblasts. Leptin is thought to act mainly through a part of the central nervous system called the hypothalamus. Until these observations, there had been no evidence that the hypothalamus had any effect on bone. Thus, this discovery reveals a previously unknown mechanism by which bone formation is regulated. Leptin, acting through the hypothalamus, may act to inhibit bone formation in some conditions of bone loss. Thus, if drugs can be designed to block leptin's action, they may be useful as therapies to restore lost bone.

Dietary Risk Factors for Osteoporosis

Although genetic influences are believed to account for up to three-quarters of the variation in bone mass, there is still room for the modifiable factors (including nutrition) to play an important role. Major attention has been focused on calcium and its importance to bone health, but the roles of other nutritional factors have been under-emphasized. Dietary potassium and magnesium, as well as fruits and vegetables, have been hypothesized to preserve bone mass and prevent bone loss through their effects on reducing the body's metabolic acidity. Investigators have been carefully tracking the association between dietary habits, bone mineral density, and fracture history. Greater potassium, magnesium and fruit and vegetable intake was significantly associated with greater bone mineral density and less bone loss with time. Although there has been a great deal of focus on calcium as a nutrient to preserve bone in the elderly, these research studies confirm that other nutrients and the overall composition of the diet may play a significant, long term role in bone health.

Paget's Disease

Role of Measles Virus in Paget's Disease of Bone Begins to Emerge

In Paget's disease of bone, both bone resorption and new bone formation are excessive at specific sites in the skeleton, leading to replacement of normal bone with bone that is of poor quality. This can result in pain, deformity, and increased risk of fracture at these sites. Recent research findings suggest that viral infection can be an important causative factor in Paget's disease. Compared to normal osteoclasts, the cells carrying one particular measles virus gene were larger and resorbed bone more actively, resembling the abnormal osteoclasts from lesions in Paget's disease. The study suggests that the virus may initially infect adult bone marrow stem cells and then get passed on to all of the different types of cells that arise. Because these cells divide to produce more cells throughout the life of an individual, this could explain the chronic nature of Paget's disease. If only a few cells are infected originally, it could explain why Paget's disease typically develops late in life and only in a few specific places in the skeleton. These research results open the way to a concerted effort to understand the cause of Paget's disease.

Osteoarthritis

Altered Cartilage Metabolism Linked to Knee Osteoarthritis

Osteoarthritis is the most common form of arthritis in the United States. It is a major contributor to reduced function and loss of independence in the elderly. Several studies have added significantly to our understanding of the factors that predispose individuals to developing osteoarthritis, particularly of the knee. Factors include obesity, age, injury to joint structures called menisci or cruciate ligaments, repetitive trauma to the joints, congenital malformations, presence of calcium crystals in joints, and undefined genetic factors. It is unclear at what age most patients begin to develop osteoarthritis, since radiologic measurements are relatively insensitive. Cartilage and bone are highly dynamic structures that demonstrate metabolic and structural changes in osteoarthritis. Recently, researchers undertook a study to determine whether cartilage and bone metabolism was altered in daughters whose mothers had osteoarthritis. The results showed that cartilage degradation was significantly increased in daughters whose mothers had knee osteoarthritis. This finding suggests that predisposition to the development of osteoarthritis begins in the early decades of life. This has important implications for identifying individuals potentially susceptible to osteoarthritis in later life. Further, this study demonstrates the utility of a marker of metabolic processes in cartilage, such as degradation, to assess osteoarthritis risk.

The Role of Joint Injury in Young Adults in the Development of Osteoarthritis

Previous studies investigating the association of joint injury with the development of osteoarthritis have examined this association in middle-aged and elderly adults. For the first time, researchers supported by the NIAMS examined this association in young adults who were followed for more than three decades. The overall incidence of knee osteoarthritis by 65 years was more than doubled in participants with a history of knee injury compared to those without a history of injury. Joint injury at entry into the study or during follow-up substantially increased the risk for subsequent osteoarthritis.

Young adults with joint injuries are at considerably increased risk for osteoarthritis later in life, and should be targeted in the primary prevention of osteoarthritis. This calls for further research to develop improved ways to diagnose and treat joint injuries before the development of osteoarthritis. In addition, it underscores the need to optimize youth coaching and training regimens, and to increase the use of proper sports equipment under safe conditions to prevent joint injuries. If successful, these changes would have tremendous impact on the individual, and result in large cost-savings for society.

Sports and Personal Fitness Issues

Genetic Markers for Tendon and Ligament Repair

Injuries to ligaments are a common and potentially costly public health problem. Such injuries at the knee often occur in sports activities, and have been reported to be the most common injuries encountered by orthopaedic surgeons. The resulting instability following injury can result in functional disability and lead to the development of degenerative osteoarthritis. Injuries to the knee's extra-articular ligaments (the supporting bands outside of the joint that function to stabilize it) in isolation generally heal spontaneously, whereas the knee's intra-articular ligaments (the supporting bands inside of the joint that function to stabilize it) do not. This poor healing potential has been related to the latter's anatomic location and to an intrinsic difference in their component fibroblasts. As such, these injuries, often need to be surgically reconstructed to restore stability and prevent degenerative osteoarthritis. This is particularly true for the anterior cruciate ligament (or ACL, one of the supporting bands inside of the joint that functions to keep the shin bone from moving forward in relationship to the thigh bone). Previous work has demonstrated biochemical differences between the ACL and medial collateral (or MCL, one of the supporting bands on the inner side of the joint that functions to keep the joint from bending inwards). Primary cells from the ACL proliferate and migrate at a slower rate than those from the MCL. NIAMS-supported researchers have also recently demonstrated that this difference in proliferation potential was the result of differences in the expression of specific genes in these ligaments. This study opens a new avenue of research in the development of techniques and reagents to study the differences between two periarticular tissues (i.e., the patellar tendon and the ACL) that differ in their ability to self-repair. Potential benefits include: (1) making possible the use of specific gene markers to study changes in gene expression in patellar tendon cells after reconstruction of the ACL; (2) opening new avenues for the use of gene therapy in the repair of ligament injuries, especially those of the ACL; and (3) offering further explanation as to why some ligaments have the ability for self-repair and others do not.

Tissue Engineering in Articular Cartilage Repair

Articular cartilage injuries are frequent, surgically challenging, and despite the best treatment, sometimes progress to end-stage osteoarthritis. This generally relates to articular cartilage's inability to heal itself. Although many treatments have been proposed and are currently in use, tissue engineering, the use of living cells with or without a biodegradable matrix, shows great promise in the treatment of this injury. The use of a periosteal flap (a piece of the tissue overlying a bone that is lined with cells that are capable of producing new bone) is one of several proposed methods to repair articular cartilage injuries that have been developed. To better understand the molecular and cellular events in this process, scientists used an animal model and determined that a particular growth factor, bone morphogenetic protein-2 (BMP-2), played a significant role. Cartilage repair is a form of tissue engineering which shows great promise for the repair of damaged articular cartilage. Since BMP-2 is known to influence the development of articular cartilage, these observations suggest an important potential role of BMP-2 as a regulator of these early events in cartilage repair. In addition, these findings may be important in defining the molecular mechanisms of fracture healing. Further study is needed to prove this regulatory function. In addition, it will be important to determine at which point in the cascade of events during the induction of cartilage formation, that BMP-2 acts and which factor(s) regulate it or are regulated by it.

Muscle Biology and Muscular Dystrophies

Facioscapulohumeral Muscular Dystrophy or FSHD

FSHD is the third most common genetic disease of skeletal muscle. It has an estimated frequency of one per 20,000. FSHD is inheritable, and a child of either sex has a risk of 50 percent of inheriting the disease from an affected parent. The inheritance of the disease inevitably leads to the expression of symptoms, which include progressive weakening of the muscles of the face, shoulder blades, and upper arms. The specific cause of FSHD is not yet known, but most often it has been associated with a mutation toward the terminal end of the DNA strand of chromosome 4. In May 2000, the NIAMS together with the National Institute of Neurological Disorders and Stroke (NINDS), the NIH Office of Rare Diseases, the FSH Society, Inc., and the Muscular Dystrophy Association of America, co-sponsored a scientific conference on the cause and treatment of FSHD. Researchers from the U.S., Canada, Europe, South America and Asia met on the NIH campus to share their latest findings and identify exciting directions for future studies on this disease.

The recommendations that emerged from the conference fall into several categories, including efforts to enhance our understanding of the molecular processes and tissue changes associated with FSHD; ways to explore possible therapies to treat the disorder; and strategies to promote the establishment of population-based studies of the disease, as well as needed research resources. The NIAMS and the NINDS have already used the recommendations from this meeting in developing and issuing a Request for Applications in FSHD in November 2000. In addition, the NIAMS and the NINDS have recently funded a research registry for FSHD and another form of muscular dystrophy known as myotonic dystrophy. The long-term goal of the registry is to facilitate research in FSHD and myotonic dystrophy by serving as a liaison between families affected by these diseases who are eager to participate in specific research projects, and investigators who are interested in studying these disorders.

Duchenne Muscular Dystrophy or DMD

Despite advances in knowledge to date on DMD, the life expectancy and quality of life for a child with DMD has not had substantial improvement since the gene was discovered in 1986. The Parent Project for Duchenne Muscular Dystrophy Research worked with the NIH to promote research relevant to potential therapies, to encourage new scientists into the field of muscle biology research and to conduct research on DMD, and to promote the importance of muscle research. The NINDS, the NIAMS, and the Office of Rare Diseases sponsored a workshop on the Therapeutic Approaches for Duchenne Muscular Dystrophy (DMD), in May 2000. An international group of multidisciplinary scientists participated in this workshop. Representatives of the French and U.S. muscular dystrophy associations were present, as well as parent representatives from the U.S. Parent Project for Duchenne Muscular Dystrophy Research and a German foundation. The goals of this workshop were to address key questions in improving treatments for DMD and identify areas of needed scientific knowledge, impediments, and critical next steps to promote effective therapy. Priorities for future efforts include: mutation detection and diagnostics; pathogenesis of muscular dystrophies, including animal models and central repositories, the role of the immune system in DMD, and heart, blood vessel, and other tissue involvement; and priorities for gene therapy research. Four key areas were identified in gene therapy research: (1) optimizing expression cassettes, (2) improving vector design, (3) managing immunologic consequences, and (4) optimizing delivery. Some of these gene therapy efforts are becoming a reality in that investigators have recently genetically engineered a dystrophin gene into muscle of a dystrophin-gene depleted model of DMD.

Skin

Impetigo

Bullous impetigo is a common infection among children aged 2 to 6. The bacterium Staphylococcus aureus, cause of the common skin infection bullous impetigo, produces a toxin that attacks a protein highly specific for cell-to-cell binding in the outermost layer of the skin, according to a new study funded by the NIAMS. Researchers have reported that breakup of this protein not only brings about the characteristic blistering, but also gives the bacterium a specific mechanism to circumvent the skin's protective barrier and spread further. Researchers determined that the toxin, exfoliative toxin A, causes impetigo's blisters when it breaks up the protein Desmoglein 1 (Dsg1), which is responsible for a specialized type of binding in epidermal skin cells. Only the Dsg1 protein is broken up and not other closely related proteins. The consequent breakdown in skin cell adhesion gives Staphylococcus a way to proliferate and cause more damage. The researchers suspected Dsg1 was the toxin's target because it is also the target of autoantibody attacks in pemphigus follaceus, a blistering skin disorder with similar cellular characteristics. The major therapy for the infection will continue to be antibiotics, even though agents that fight protein breakup might help prevent the spread of the bacterium.

The Gene Causing Pseudoxanthoma Elasticum Has Been Identified

Pseudoxanthoma elasticum is an inherited disorder characterized by progressive calcification of elastic fibers in the skin, eye and cardiovascular system. This disease is inherited and can have severe manifestations in these organ systems. A better understanding of the disease has been hampered by lack of information as to the underlying cause which now, it is hoped, will be corrected with the identification of the gene causing the disease. In the first step to finding the gene, a large collaborative group of investigators used a population genetics approach to narrow the location of the gene to a portion of human chromosome 16 (16p13.1), and one gene in this region (MRP6) was later determined to be the gene associated with the disease. Work is continuing to determine the function of the gene and how mutations in the gene result in the clinical disease. This discovery should allow for the eventual determination of the cause and, ultimately, allow the design of therapeutic interventions for the treatment of this disease.

Gene Therapy for Skin and Systemic Diseases

Gene therapy is a technology whose time is coming. Skin is an ideal organ for gene therapy because of its accessibility. In particular, skin provides an outstanding opportunity for direct treatment by introducing genetic material using vehicles other than viruses. One area of great promise is in research on basal cell skin cancer. Basal cell skin cancer is the most common cancer in the United States. It very rarely metastasizes and is a good model system for investigating gene therapy approaches. It is also superficial and recognizable in the skin and, therefore, was the subject of a study using direct injection of DNA coding for an immune stimulatory molecule (interferon alpha2). In an animal model in which the human cancer was transplanted to an immune deficient mouse, the DNA was injected complexed to liposomes. It was demonstrated that the DNA induced the production of the interferon alpha2 and, more importantly, the interferon alpha2 induced the regression of the skin cancer. This has potential for direct human application in the non-surgical treatment of this most common cancer in the U.S.

Topical treatment with DNA has the potential of penetrating the skin, probably through hair follicles, to exert an effect in the living skin and beyond. In a study of topical application of DNA in a water solution, it was demonstrated that DNA that encodes the hepatitis B surface antigen applied in this way could induce a response similar to that produced by the intramuscular injection of the commercially available vaccine. It was also demonstrated that intact hair follicles were necessary for the local application of this water solution of the genes to allow penetration and expression of the protein and, thus, the positive vaccination equivalent result.

Wound Healing: From Tissue Culture to Human Grafts

The healing of chronic wounds is a major health problem in the United States. This occurs in both the elderly and in the very young with specific skin diseases. Our understanding of the way the various layers of skin adhere to one another has been a major advance that has come out of basic laboratory investigations of hereditary skin diseases, and it is now being applied to the development of more effective means for treating chronic wounds-whatever the cause. In addition, a major cause of chronic wounds, particularly in the elderly population, is inadequate circulation. However, it is not clear whether oxygen supply at the wound site itself has a positive or negative influence in wound healing.

Low oxygen tension had been shown to stimulate cell growth and to stimulate the synthesis of certain growth factors and components important in wound healing. In a recent study using a tissue culture model to simulate acute wounding and with analysis of oxygen tension (the amount of oxygen available) it was demonstrated that oxygen tension dropped in the areas of model wounds as compared to the unwounded areas of the culture, but interestingly, that the oxygen tension decrease was blocked by inhibitors of cellular protein synthesis. This would indicate that the drop in oxygen tension is the result of increased cellular activity as a wound- healing response, rather than being the cause of the wound. It provides theoretical support for hyperbaric (high pressure) oxygen and other treatments designed to increase oxygen supplied to the tissue from the outside.

Alopecia Areata

Advances in Understanding Hair Development and Treating Hair Diseases.

Hair is a skin appendage present in most mammals. It grows in cycles in all hair bearing animals under the control of a number of genes and influenced by a number of proteins. A number of skin diseases affect this hair cycle resulting in various abnormal types of hair loss as well as the hair loss normally associated with aging. An understanding of the events in hair development, cycling and the mechanism of hair loss in various diseases will allow for the development of treatments to correct these abnormalities.

Animal models are widely used in the study of hair, particularly mouse models. In one investigation, a common protein (TGF ), which has been implicated in a number of diseases, was investigated for its role in hair follicle development. It was demonstrated that one type of this molecule, the TGF 2, plays a role in hair follicle development and induces the beginnings of hair follicle formation. Other forms of TGF do not seem to play a role. The absence of hair in a widely studied hairless mouse is due to a specific gene defect termed hairless. It has been shown that these mice are hairless because the hair regresses after the first hair cycle. Investigating the hair cycle in these animals has demonstrated that it is the improper regulation of the onset of involution of the hair follicle after the first growing cycle that results in a permanent loss of hair in these animals. While the gene has been isolated, it is not yet clear how this gene acts to cause the abnormality in these mice. Knowledge of the molecular mechanisms involved in the continuously repeated cycle of resting, shedding, and regrowth means that hair biology is useful not only as a way to understand hair diseases such as alopecia areata, but also for understanding of other cycling and regenerating tissues. The formation of the hair follicle and its cyclical growth and regeneration depends upon reciprocal signaling between the outer and deeper layers of the skin. Looking at molecules previously identified from studies of skin cancers (basal cell cancers and the nevoid basal cell carcinoma syndrome), it was demonstrated that certain signaling proteins (the Wnts), but not other molecules (Sonic hedgehog), are necessary for the maintenance of the growing phase of the hair follicle and for its induction. In contrast, both of these molecules are involved in the formation of certain skin cancers.

This increased understanding of the hair follicle system and the chemicals and signaling molecules involved in its cycling will allow the development of specific interventions to treat hair diseases, both naturally occurring such as alopecia areata and those induced by certain cancer chemotherapeutic treatments. The mouse model system provides a useful method for screening potentially useful treatments of the human disease.

The disorder alopecia areata is an acquired loss of hair that can be quite severe and disfiguring. In two recent studies, animal models were used to demonstrate that a widely used treatment for the human disease, topical diphencyprone, also works in these animal models. This will allow investigation of the mechanism of action and, hopefully, the ability to improve its success in the human disease. Other studies with these and other mouse models with hair loss similar to alopecia areata are allowing for the determination of the specific genes involved in the disease and/or susceptibility to it. With this knowledge in hand, a better understanding of the human disease and, therefore, better approaches to its therapy are to be expected.


Story of Discovery – Research Progress Through the Prism of One Scientist

While there are many ways to view scientific progress over time, one fascinating view is through the prism of a successful scientist – one who has struggled to unlock the mysteries of diseases and has triumphed and truly made a difference in the lives of patients and their families.

Dan Kastner came to the NIH in 1985 having many achievements – he had both an M.D. and a Ph.D. and had finished a residency in Internal Medicine. When he reached the NIH campus as a beginning research Fellow, he joined the renowned NIAMS Intramural Research team that was studying the genetics of lupus in mice. Dr. Kastner also saw patients in the NIAMS clinic, and one particularly intriguing patient was the catalyst for turning his career around. This young Armenian man had had episodic arthritis with swelling and pain and debilitation since infancy. He had been to many different doctors, but the cause of his illness remained a mystery. After consultation with his NIH colleagues, Dr. Kastner explored the possibility that the young man might be suffering from Familial Mediterranean Fever (FMF). After a series of laboratory tests, Dr. Kastner administered colchicine, a drug recognized for its ability to help people with FMF, and the young man's symptoms were indeed ended in a life-changing way.

Meanwhile, back in the laboratory, things were not quite so successful. The working hypothesis in the lupus mouse study was proven wrong and the laboratory project to be pursued was suddenly not very clear. Dr. Kastner reflected on his desire to combine his research pursuits so that the patients he saw as a physician would also be the basis of his research in the laboratory. He was a true model of bench to bedside and bedside to bench research. Over the next twelve years, he mastered the art of translational research.

Dr. Kastner returned to his experience with the FMF patient and, coupled with his interest in genetics, began the pursuit of studies on the genetic basis of FMF. The year was 1989 and the scientific community was excited about the possibilities of identifying disease-causing genes. The challenge was to identify enough families affected by FMF to conduct genetic studies, so Dr. Kastner worked with local Armenian churches and with a clinic outside of Tel Aviv, Israel, where the disease occurs more frequently than in the U.S. The summer of 1989 found Dr. Kastner in Israel collecting blood samples both in the Israeli clinic as well as people's homes. People were happy to participate since many had seen family members die of FMF and were worried for themselves and their children. Samples were taken from about 350 people that summer, and cell lines were grown from each person (the technology used at that time). This was a huge undertaking for Dr. Kastner and his colleagues.

Dr. Kastner then returned to the U.S. and launched his study to identify the chromosome on which the gene for FMF resides. After more than a year-and-a-half of intense research, the location of the gene was determined to be on chromosome 16. The next years were spent narrowing down the region of analysis. In 1997, Dr. Kastner identified the actual gene that causes FMF. With the techniques available today, this process would have been shortened considerably – cells no longer need to be grown – the DNA can be extracted from the blood samples. Furthermore, the genetic information available today through mapping and sequencing efforts means that much more is known about all human chromosomes than was the case a decade ago.

Once the gene was identified, there was an immediate, practical impact. Lots of samples from around the U.S. were sent to the NIH for analysis to determine if previously undiagnosed people suffering from periodic fevers had FMF. Many people were subsequently treated with colchicine and their lives were tremendously changed as their debilitating symptoms of many years were ended. There are still many unanswered questions about the actual cause of FMF, and biochemical and cell biology studies are revealing a completely new perspective on inflammation that is the focus of cutting edge research today.

In the case of FMF, the gene that is affected holds the code for making a protein called pyrin. It is thought that pyrin normally plays a role in keeping inflammation under control, and mutations in the gene may lead to the production of a malfunctioning protein and uncontrolled inflammation. Knowing the gene that causes a disease can help researchers to develop treatments. When the disease process has been revealed, specific treatments can be created for patients, developing medications to affect various aspects of the disease process.

When one research question is answered, invariably countless more questions remain unanswered and are just waiting to be pursued. In one example of this, Dr. Kastner and his colleagues recognized that there were still patients who had many of the symptoms of FMF, but did not fit the whole profile, and did not have the mutation on the culprit gene on chromosome 16. He and his team ultimately identified a second group of
people with inherited inflammatory disorders. In these patients, the genetic mutations are on chromosome 12, and the mutations involve a cell surface receptor for the inflammatory protein tumor necrosis factor (TNF). Normally, the TNF receptor plays a role in the body's defenses against infectious and foreign agents. Receptor mutations are thought to predispose people to severe inflammation. This discovery marked the first time that TNF receptor mutations were tied to an inherited disease, and opened up the possibility of improved treatments, targeted at the cellular level, for many of the immune-related and inflammatory disorders.

The NIH and the broad scientific community are indeed fortunate to have many scientists with Dr. Kastner's vision, love of a good medical mystery, flexibility in what avenues they will pursue when one avenue leads to a dead-end, and ability to capitalize on the latest technologies and techniques. They are driven by a desire to improve the scientific enterprise and improve public health in a way that will affect daily life for millions of Americans. We look back more than a decade to see these stories emerge, and we look forward with eager anticipation to the next decade as Dr. Kastner and others continue to pursue fascinating medical mysteries in genetics, rheumatic diseases, and the many diseases of periodic fevers and inflammation.

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. Perhaps most noteworthy, we are making significant progress in our efforts to prevent disease in the first place. The ultimate conquest of diseases always involves research across a broad spectrum -- from basic to animal models to clinical trials to prevention research. In most cases, the essential ingredient is the translation: clinical research without the basic foundation is very limited in scope and effectiveness, and basic research that is not translated into clinical studies misses the opportunity to improve public health. Stories of the interplay of research across many disciplines, across the full spectrum -- stories of progress and promise supported by the NIAMS are stories of which we are proud.

Since the NIAMS was established, significant progress has been realized from the investment in research on arthritis and musculoskeletal and skin diseases. We are on the brink of discoveries that can revolutionize health care and the treatment of chronic illnesses. NIAMS-supported researchers are today uncovering important pieces of the research puzzle and are launching research initiatives to take advantage of emerging areas of science. NIAMS research has ramifications for this generation and generations to come. We are investing in the future health of our nation, and American people of all ages and population groups will benefit from these investments.

Budget Policy


The Fiscal Year 2002 budget request for the NIAMS is $443,565,000, including AIDS, an increase of $46,962,000 and 11.8 percent over the FY 2001 level, and $94,316,000 and 27.0 percent over FY 2000.

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

FTEs by Fiscal Year.

Funding Levels by Fiscal Year.

One of NIH's highest priorities 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 providing new research opportunities. The Fiscal Year 2002 request provides average cost increases for competing RPGs equal to the Biomedical Research and Development Price Index (BRDPI), estimated at 4.3 percent. Noncompeting RPGs will receive increases of 3 percent on average for recurring direct costs. In FY 2002, total RPGs funded will be 1,025 awards, an increase of 75 awards over the FY 2001 Estimate, the highest annual total ever awarded.

Promises for advancement in medical research are dependent on a continuing supply of new investigators with new ideas. In the Fiscal Year 2002 request, NIAMS will support 272 pre- and postdoctoral trainees in full-time training positions. An increase of 10 percent over Fiscal Year 2001 levels is provided for stipends and training-related expenses (e.g., health insurance, research supplies and equipment, and travel to scientific meetings).

The Fiscal Year 2002 request includes funding for 34 research centers, 157 other research grants, including 8 new clinical career awards, and 34 R&D contracts. The R&D contracts mechanism also includes support for 9 contracts for the Extramural Clinical and Pediatric Loan Repayment Programs.

Additional funds have been included within the Research Management and Support mechanism for increases in several areas. First, additional FTEs have been requested for review and management of new applications in targeted areas, such as clinical and autoimmunity research. Second, additional funds have been provided for expanded activities in information technology; specifically for enhanced IT security, implementation of administrative databases to assist workflow management, and design services and management of the NIAMS website. Third, funds have been included within this category for expanded information dissemination activities. These activities include the opening of a community health center for underserved populations in Washington, D.C., as well as wider distribution of NIAMS publications to the general public and special needs populations through a centralized distribution mechanism.

The mechanism distribution by dollars and percent change are displayed on the following charts.

FY 2002 Budget Mechanism pie chart.

Bar chart showing FY 2002 Estimate Percent Change from FY 2001 by Mechanism.