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Further research 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 was an unexpected observation, as collagen is considered to be a product of fibroblasts that are normally found in the dermis below 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 the upper part of the dermis below the basement membrane itself. This investigation is helping us to understand precisely how these molecules work to attach the epidermis to the dermis.

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The Epidermolysis Bullosa Registry has now collected enough patients for specific research projects. In one study, recessive dystrophic EB patients have been genotyped. They demonstrated a higher than expected association with certain HLA markers. eventually aid in the localization and later isolation of the gene causing the disease. In another study, the Dowling-Meara form of EB seems to be in high enough prevalence within the registry data to make a reverse genetic linkage analysis feasible to search for the gene. The registry material is being analyzed to determine whether or not a full-blown genetic linkage analysis is feasible at this time.

The availability of patients through the registry should facilitate an efficient mounting of clinical trials when appropriate promising agents become available in the future. The Epidermolysis Bullosa Registry is now undergoing recompetition for an additional five years of funding. The new funding period will include not only a continuation of existing objectives but also an expansion to include: 1) epidemiologic and biostatistical analysis of the data base thus far collected, 2) clinical trials where appropriate, and 3) support for the banking of appropriate tissue to facilitate future basic science investigations of genetic and other pathogenic mechanisms of epidermolysis bullosa.

WOUND HEALING

Last year,

Mr. Stokes: Wound healing. Controlling the formation of scar tissue is still an area in need of research.

NIAMS indicated that it wished to advance research in this area, What activities are you currently pursuing in this area? What level of funding was provided in FY 1991?

Dr. Shulman: Currently, the NIAMS is working to develop acoustic methods capable of making objective noninvasive clinical measurement of material properties for surgical wounds. Initial studies have shown that high frequency ultrasound is a promising modality well-suited for making such noninvasive measurements in humans. Up to 10 percent of all surgical patients experience wound complications which result in increased hospital costs and lost productivity amounting to more than a billion dollars per year. The NIAMS estimates the funding level in this area for FY 1991 will be approximately $800,000.

Mr. Stokes: What activities and funding have been proposed in this area for FY 1992?

Dr. Shulman: The NIAMS is planning a workshop in FY 1992 to stimulate interest in this important area of wound healing and expects to fund additional research project grants for a total estimated funding level of $1.2 million.

RHEUMATOID ARTHRITIS

Mr. Stokes: Rheumatoid arthritis is a major health problem affecting over 2 million Americans. Women are three more times likely than men to be affected. What is some of the research being conducted in this area?

Dr. Shulman: Among the research advances in rheumatoid arthritis this year is the identification of the cell in the synovial membrane--joint lining--that produces collagenase, Employing the new techniques of in situ hybridization, the cell was found to be the Type A lining cell of the synovial membrane. It is the collagenase that destroys collagen in bone and cartilage in rheumatoid arthritis.

Recent basic research has yielded a better understanding of mechanisms involved in the development of arthritis. One of the most promising advances this year is T cell vaccination. Working with rats, NIAMS-supported scientists induced arthritis and then prepared suspensions of T cells--a type of white blood cells-- obtained from the rats' blood late in the course of disease. After in vitro treatment, the T cells were injected into disease-free rats. These rats proved to be resistant to arthritis. The successful use of T cells from diseased animals to help healthy animals is a key breakthrough for achieving the next step: development of protocols for T cell therapy and vaccination in humans.

NIAMS funds three Specialized Centers of Research in Rheumatoid Arthritis. These centers are focussing on unraveling the complex immune phenomena characteristic of established rheumatoid arthritis, the nature of the destructive reactions unleashed to inflame and

destroy cartilage, and clinical advances for the patient with rheumatoid arthritis. Examples of recent scientific accomplishments in the specialized centers are:

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Specific cellular and molecular events initiating and perpetuating joint damage in rheumatoid arthritis are being determined. This includes investigating the earliest alterations that transform immune cells to a destructive role. The interplay of genetic and environmental factors appears important.

o Magnetic resonance imaging--MRI--is being used to assess

articular damage of patients with rheumatoid arthritis during
treatment with different drugs. With MRI, bony changes can
be seen much earlier than with conventional x-rays.

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Pain and function in patients with rheumatoid arthritis are
influenced by psychological factors more than by disease
state and researchers are matching the patients coping skills
with the disease state. Biochemical markers of coping are
being evaluated.

There are also examples of research accomplishments from the multipurpose arthritis and musculoskeletal centers as follows:

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Cell wall fragments from several strains of bacteria common to the human gut have been shown to produce a chronic, erosive, recurrent polyarthritis in a rat model, suggesting that normal gut bacteria may be an environmental trigger for rheumatoid arthritis.

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Studies of the genetics of human autoantibodies suggest that autoantibodies are relevant to the normal immune response and not a product of renegade mutation.

Mr. Stokes: Is there any explanation as to why the disease seems to subside in pregnant women?

Dr. Shulman: Rheumatoid arthritis is a puzzling disease in that it can flare up and then subside. The arthritis frequently subsides during pregnancy. To learn more about this interesting phenomenon, scientists analyzed blood obtained from mother and child in 43 pregnancies. They tested the blood for certain genetic protein markers. In those pregnancies where the arthritis subsided, scientists found that the genetic markers of mother and child were frequently dissimilar, whereas the markers were similar in those pregnancies during which the arthritis did not subside. The scientists postulated that the mismatch induced an immunologic reaction that suppressed the arthritis.

REPETITIVE MOTION SYNDROME

Mr. Stokes: Repetitive motion injuries account for a large proportion of the nation's occupational illnesses. If fact, during the department of education's hearings, the National Technical

Institute for the Deaf testified that many interpreters suffer with this type of injury. What research efforts are underway in this area?

Dr. Shulman: Within a Multipurpose Arthritis and Musculoskeletal Center, the NIAMS supports a project on occupational rheumatology researching repetitive motion injury, such as, carpal tunnel syndrome. Repetitive motion syndrome is a complex disorder involving repeated motions, weight, and repetitions; that is, light loads with many repetitions or heavier loads with fewer repetitions. It occurs in different industries, such as meatpacking, automobile nanufacturing, and computer usage. This condition was minimally reported five to ten years ago. At the present time, there are few grant applications targeted to repetitive motion syndrome. The NIAMS has a research project involving the biomechanics of motion and force of the extremities and of the spine in grocery store cashiers. The NIAMS intends to convene a advisory workshop with experts for advice on how to proceed in this new field.

Mr. Stokes: What level of funding would help you to stimulate research in this area?

Dr. Shulman: I believe that there are promising research opportunities to conduct epidemiologic studies, clinical investigations, and basic research in repetitive motion syndrome. If we can stimulate research in this area, we plan to fund an estimated $2 million of meritorious research efforts.

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RPG'S - AVERAGE COST INCREASE

Mr. Early: What is the average increase in the size of noncompeting research project grants under the budget proposal? What about new and competing research grants?

Dr. Shulman: The average increase in the size of noncompeting research project grants is 0.7 percent for noncompeting and 5.5 percent for new and competing.

Mr. Early: What was the downward negotiation rate for competing grants in FY 1989 and FY 1990?

Dr. Shulman: The downward negotiation rate was 12 percent in FY 1989 and 12.2 percent in FY 1991.

Mr. Early:

What are you projecting for FY 1991?

Dr. Shulman: Fiscal year 1991 is a transition year for the NIH for implementation of "A Plan for Managing the Costs of Biomedical Research." Competing research project grants will continue to be reviewed in a two-step process; first by the Initial Review Groups and then by the scientific staff of the Institute. There will be no across-the-board reductions; however, budget adjustments will be made on a grant by grant basis.

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Dr. Shulman: The downward negotiation rate in FY 1989 was 11.9 percent and in FY 1990 it was 12.2 percent. In FY 1991 noncompeting grants are increased an average of 4 percent over the FY 1990 award.

Mr. Early: 'What is the BRDPI for these years?

Dr. Shulman: The Biomedical Research and Development Index-BRDPI--for FY 1989 was 5.20 percent, for FY 1990 it was 5.80 percent, and for FY 1991 it is 5.99 percent.

Mr. Early: Doctor, doesn't this institutionalize the large downward negotiations the Institute has had to make in competing grants these past few years?

Dr. Shulman: I believe that the BRDPI is a good indicator to reflect patterns of expenditures in biomedical research. Using the BRDPI to project future costs of research is a reasonable approach.

Mr. Early: Will the NIAMS be able to fund noncompeting grants at the commitment level under the FY 1992 request? New and competing grants at the peer reviewed levels?

Dr. Shulman: The NIAMS plans to fund research project grants as close as possible to their approved commitment levels for noncompeting grants and their peer-reviewed level for competing

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