Regarding out of order funding, we use it to stimulate areas of research that need more attention and also to explore innovative ideas. Decisions to fund out of order are made on both a programmatic and scientific basis.

The

With regard to the length of grants, the NIAMS has no grant mechanism for longer than five years. However, we are concerned that a four year average may require us to shorten grants, such as the First Independent Research Support and Transition (FIRST) Award. definition of this grant is "To provide a sufficient initial period of research support for newly independent biomedical investigators to develop their research capabilities and demonstrate the merit of their research ideas." With the complexity of research today, I believe that it is important to provide grant periods up to five years to allow investigators enough time to be productive; and an average duration between four and five years would seem to be a wise policy.

OTHER BUDGET

Mr. Early: I see that you plan to increase the number of research career program awards in FY 1991 by 23. In what areas are you planning increases, and why do you feel this is necessary or desirable?

Dr. Shulman: It is necessary to increase research career awards to support qualified basic and clinical research scientists who will be needed in coming years to take advantage of the new discoveries uncovered by the increasingly powerful technologies used today. There is a need for more research career awards in all the fields within the NIAMS's mission, especially in the areas of osteoporosis, lupus, and basic and clinical research on skin diseases.

Mr. Early: For FY 1992 you are proposing a substantial decrease in resources (funds) for the category identified as "other related research." What types of activities does your institute generally support under this mechanism? What activities will be affected by

this decrease?

Dr. Shulman: The other related research category supports Conference Grants, Research Demonstration and Dissemination Project, Small Instrumentation Grants, and Scientific Review and Evaluation Grants. Small Instrumentation Grants will be decreased from 19 awards at $480,000 to six awards at $147,000 due to the emphasis on research intensive grants.

Mr. Early: What was the NIAMS Professional Judgment Budget and how does it differ from the request before us?

Dr. Shulman: The NIAMS Professional Judgment Budget was $300,693,000. This would increase the number of investigator initiated competing research project grants from 219 to 415. The number of centers would increase by 10, from 26 to 36 including four

additional skin diseases research centers and more specialized centers of research and multipurpose arthritis and musculoskeletal centers. The number of research career awards would increase by 17 and research trainees would increase from 228 to 299. Our Intramural Research program would support expansion of the Laboratory of Structural Biology Research and a new Laboratory of Connective Tissue Biology. Our Research Management and Support program would increase to support the additional staff necessary to provide the scientific leadership and overall management direction of the entire Institute.

INITIATIVES LOST

Mr. Early. Will any significant new research initiatives or opportunities be lost or delayed by lack of funds in the FY 1992 budget request?

Dr. Shulman. The Institute currently has unfunded meritorious applications in the full range of its categorical responsibilities. Some of the research needs and opportunities for the future, which could be undertaken with additional funds, are listed below.

Osteoporosis.

Increased research emphasis is needed on the effect of growth factors and other regulators on bone metabolism; the development of animal cell culture models; the role of mechanical/gravitational stress in maintaining bone mass and preventing bone loss; the mechanism of action on bone of factors with therapeutic potential, such as fluoride, estrogen and other hormones, and bisphosphonate; the roles of bone architecture and strength in osteoporotic fractures; and identification, characterization, and molecular mechanisms of action of receptors for hormones, growth factors, and cytokines active in bone cells.

Lyme disease.

Additional research is needed to increase understanding of how the infectious agent causes the disease, with the goal of improving both diagnosis and treatment, and providing the scientific basis for development of an effective vaccine.

Systemic lupus erythematosus. An intensive research effort is needed to investigate genetic factors and to conduct epidemiologic studies to define the reason for the female and minority predominance of lupus. The potential viral cause of lupus as well as clinical studies to improve treatment need to be further explored.

Spondyloarthropathies.

In 1990 the human HLA B27 gene, known since 1973 to be associated with spondyloarthropathy, was successfully transplanted into a strain of laboratory rats, and the rats developed the equivalent of the human disease. This was striking proof of the importance of the gene in the causation of the illness. However, a trigger factor, thought to be either gastrointestinal or genitourinary infection, has not yet been implicated. The new animal model, and other studies directed specifically at infectious triggers, provide exciting opportunities to solve the mysteries of this group of arthritic diseases.

Rheumatoid arthritis. There are new research opportunities to investigate the specific genetic markers for rheumatoid arthritis that remain to be funded. Promising research on nontoxic means of neutralizing immune cells for the disorder should also be pursued.

Arthritis in children. Progress in understanding the maturation of immune responses in children could yield valuable information on the development of arthritis in children. Current studies suggest that a double dose of the genes that make one susceptible to rheumatoid arthritis may contribute to its earlier onset.

Scleroderma. Further elucidation of the abnormalities of vasoregulation that occur in Raynaud's phenomenon, often the first symptom of scleroderma, may contribute to our understanding of the etiology of this disease.

Sjogren's syndrome. Recent investigations have uncovered the presence of a retrovirus in some patients with Sjogren's syndrome. Additional research is needed to explore the relationship between genetic and viral factors in human autoimmune disease.

Heritable disorders of connective tissue. Studies are needed to utilize the powerful techniques of modern molecular biology to isolate genetic defects and to study structure-function relationships in connective tissue macromolecules and the way in which mutations alter molecular structure, function and processing. Additional research is also needed to capitalize on research describing a new animal model for osteogenesis imperfecta, discovery of the gene location for Marfan's syndrome, and elucidation of a basic collagen defect in the etiology of epidermolysis bullosa.

Osteoarthritis. For the first time, a gene has been found that causes one form of osteoarthritis. This could lead to the prospect of recognizing who is at risk for osteoarthritis and developing treatment measures to prevent joint destruction. Other promising research opportunities deal with differences between types of osteoarthritis, population differences, the role of trauma in disease development, and the role of ligaments and tendons in disease development.

Low-back pain. Research opportunities in the area of low back and other types of spinal pain are concerned with: analysis of the neurophysiology of spinal pain; physiologic and social determinants of back pain; studies of new imaging methods for diagnosis, such as magnetic resonance; and muscle training and its role in rehabilitation and prevention of back pain.

Paget's disease. Paget's disease is a chronic disease of the skeleton resulting in bone that is dense, but fragile. Efforts should be directed toward isolating specific local and systemic factors that may be altered in the disease state, discovering whether there is a genetic rationale to the familial and racial patterns of the disease, and developing animal models of the disease process.

Muscle biology. Additional research is needed to explore the mechanisms that cause skeletal muscle to atrophy when it is rested for extended periods of time and hypertrophies when it is exercised. The molecular and physical mechanisms of feedback control of both muscle atrophy and hypertrophy need to be investigated.

Musculoskeletal fitness and sports medicine. In April, 1991 the NIAMS, in conjunction with the National Advisory Board of the Institute and the Centers for Disease Control sponsored a conference on Surveillance Strategies for Sports Injuries in Youth, which addressed how such a system can be implemented, operated and applied to prevent sports injuries in the younger segment of the population. Additional research is also needed in the repair of injuries, soft tissue inflammation related to injury, and the biomechanics of falls and injuries.

Epidermolysis bullosa. Epidermolysis bullosa is a group of uncommon blistering diseases involving the skin and mucous membranes. Recent advances have discovered a defect in one of the forms of collagen which anchor the layers of skin to one another. While the primary cause of the illness and potential treatments remain unidentified, advances in molecular biology and molecular genetics are making it possible to apply new approaches to causal mechanisms.

Keratins. Scientists in the NIAMS' new Laboratory of Skin Biology have recently isolated a gene that is responsible for the production of loricrin, one of the four major proteins produced by epidermal cells. This finding makes possible studies to compare genetic data obtained from patients with epidermal disorders to determine if loricrin gene structure or function is altered in specific heritable cutaneous disorders, such as epidermolysis bullosa or the ichthyoses.

Alopecia. More research is needed on the clinical and histopathologic features of alopecia areata--hair loss, and factors controlling hair growth. The autoimmune aspects of the disease should be pursued as well as the development of pharmacologic interventions.

Vitiligo. One of the most likely hypotheses for the causes of vitiligo suggests involvement of autoimmune mechanisms in the destruction of pigment cells. The trigger for the immune response is unknown, and more research is needed to address this problem.

Photobiology. Research continues to be necessary on the effects of ultraviolet radiation on the skin, including the effects of sunblockers, the effects of sunlight on the immune system, the ramifications of artificial sources of ultraviolet radiation and environmental and social changes leading to increased exposure to ultraviolet radiation.

PRIORITIES

Mr. Early: What priorities would the institute pursue if additional resources were available? If an increase over the FY 1992 request is provided, how would you use these additional funds?

Dr. Shulman: If additional funds were provided, the NIAMS would fund about 75 more competing research project grants. This would permit funding of high quality research proposals to a payline of the 30th percentile. Another high priority is the expansion of our skin diseases core research centers from the existing 2 centers to a total of 6 centers. In addition, we would propose additional specialized centers of research in such high priority areas as lupus, and additional multipurpose arthritis and musculoskeletal centers. To train and develop an adequate number of future researchers in our fields, we would increase both the research career program by 16 awards and research training by 71 trainees. The Institute would fund an additional 9 research contracts to support urgently needed clinical trials. The priorities for the Intramural Research Program would include the expansion of the Laboratory of Structural Biology Research and the development of the new Laboratory of Bone and Connective Tissue Biology.

EPIDERMOLYSIS BULLOSA

Mr. Early: What progress has been made in epidermolysis bullosa? What are the institute's plans for research on EB in FY 91 and FY 1992.

Dr. Shulman: I am pleased to report a number of new research findings concerning epidermolysis bullosa (EB). Naturally occurring animal models and genetically engineered animals with defective genes are being utilized. Patients with new and different forms of epidermolysis bullosa have been uncovered by the EB Registry. This is clearly important in constructing the design and evaluation of clinical trials for the treatment of EB.

Further research in FY 1991 and FY 1992 concerns mechanisms of attachment of the epidermis to the dermis through the basement membrane zone, which is the defective target area in EB. Advances include the determination that the anchoring fibrils, which consist of type VII collagen and which are defective in the dystrophic form of EB, can be elaborated by the epidermal cells that are located above the basement membrane. This has implications for treatment employing new techniques such as, cultured epidermal sheets.

Acquired EB, a special type of EB in which antibodies are produced to type VII collagen, has provided the source of these antibodies for use in determining exactly how anchoring fibrils function in attaching the epidermis to the dermis. These antibodies have been used to demonstrate that the end of the type VII collagen, which is not readily visible utilizing the electron microscope, is found in the lamina densa of the basement membrane zone. In contrast, the visible banded portion of the type VII collagen is in