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production to diabetics also moved forward this year when NIDDK grantees successfully used the thymus of rats as a new site for transplanting insulinproducing cells. With this approach, they enhanced both immune tolerance to grafts at other sites and graft survival.
Progress is also being made in understanding non-insulin-dependent diabetes. Glucose transport mechanisms are emerging as a major new target for potential treatment of this disease. Studies in animals are defining more precisely the cascade of molecular events involved in the production and action of insulin, in order to pinpoint how resistance to insulin occurs. related research, scientists have identified the cell receptor that binds drugs used to treat non-insulin-dependent diabetes, thus paving the way for more effective drug development. A key source of knowledge about the metabolic abnormalities and complications of non-insulin-dependent diabetes are NIDDK studies of the Pima Indians, who have the world's highest prevalence of this disease.
Applicable to both forms of diabetes are studies on the genetic
components of this disease.
Research clues are helping to narrow the search for the diabetes genes. Gene mapping strategies are bearing their first fruits of success with the identification of a linkage of a genetic locus in a rare form of non-insulin-dependent diabetes. The genetic puzzle of diabetes remains a complex challenge, however. To help meet this challenge, I am pleased to tell you that the Institute will begin a new Diabetes Interdisciplinary Research Program in 1992 in an innovative partnership with the Juvenile Diabetes Foundation, International. This follows a productive partnership previously established with the Cystic Fibrosis Foundation.
For kidney and urologic diseases research, I am pleased to report several exciting scientific events. With NIDDK grant support, kidney researchers have made inroads in understanding polycystic kidney disease (PKD), in which cyst formation can impair and destroy kidney function. Recently, NIDDK grantees discovered that the combined action of two known growth-promoting chemicals can initiate cyst formation. This finding has already resulted in the testing of candidate drugs in mice with PKD, thus opening new therapeutic windows.
In seeking to combat end-stage renal disease (ESRD), the NIDDK is supporting studies to understand the strikingly high incidence of the kidney
disease of diabetes mellitus (KDDM) among the ESRD patient population, and among Native Americans and Blacks. The NIDDK is also studying the genetic causes of KDDM in Native Americans, and is designing a therapeutic intervention study. The NIDDK-supported U.S. Renal Data System is helping to shed light on the natural history of ESRD and its precursor diseases. Based on insights already gained, the NIDDK plans to launch a pilot clinical study in 1992 on kidney disease and hypertension in Blacks. Thus, the NIDDK has intensified basic and clinical research on the kidney diseases that lead to ESRD, for which annual dialysis and transplantation costs are $5.4 billion.
Building a strong urologic diseases research program is a high priority. The NIDDK is seeking to intensify high-quality research in interstitial cystitis, a debilitating disease that primarily affects women; benign prostatic hyperplasia (BPH), which most men develop as they age; and diabetes-related urologic disorders. New knowledge about inflammatory mediators, growth factors and basic bladder function is helping to construct a solid science base in urology, from which future clinical achievements will flow. To expand research in pediatric kidney and urologic diseases, the NIDDK will soon be funding its first research center in these fields.
Achievements in blood disease research are moving steadily toward
clinical applications. The NIDDK was a major research contributor to the development of recombinant erythropoietin, a drug that has proven outstanding in alleviating the anemia of ESRD patients, and was just recently approved by the FDA for treating the anemia of AIDS patients. In preliminary clinical studies, NIDDK scientists recently demonstrated the effectiveness of the drug hydroxyurea in reducing the complications of sickle cell disease, one of the most devastating diseases of Black Americans. Now, researchers are combining this drug with other agents in attempts to extend clinical improvement. Progress has also been made toward the development of effective oral drugs to remove the excess iron that accumulates in Cooley's anemia patients as a result of frequent blood transfusions. In preliminary NIDDK-supported tests in animals, these oral chelating drugs have shown their ability to remove iron, while appearing to have low toxicity. We also support research on bone marrow transplantation as a treatment method and a vehicle for gene therapy. In digestive diseases, compelling research advances abound. A broadly
supported multicenter clinical trial has confirmed the results of the pioneering discovery by our intramural scientists that the drug interferon alfa is effective in treating hepatitis B and C. For ulcers, NIDDK grantees have developed a simple, noninvasive breath test for determining which patients have an underlying bacterial infection that can be eradicated by antibiotics. Grantees have also identified a possible marker for inflammatory bowel disease. If this marker can distinguish between the two forms of this disease--ulcerative colitis and Crohn's disease--it may help to reveal their respective causes. In other studies, the immunosuppressive drug FK506 continues to show enormous promise in liver transplantation, with fewer side effects than conventional drugs. With NIDDK support, a useful animal model was developed for primary biliary cirrhosis, which primarily affects women and is the most frequent indication for liver transplantation in adults. We are also beginning to understand the relationship between obesity and the development of gallstones, and are following closely the new surgical procedure for gallbladder removal. Malabsorption syndromes, such as celiac disease, are the focus of studies aimed at identifying factors that decrease or prevent nutrient absorption by the gastrointestinal tract. This knowledge may also be useful in addressing the wasting syndrome of AIDS.
Our nutrition program is breaking new ground in understanding nutrient metabolism and energy expenditure. Of particular concern is obesity, a disproportionate health problem in minority populations and a major risk factor for non-insulin-dependent diabetes, heart disease, gallbladder disease, and other serious illnesses NIDDK grantees are searching for obesity-related genes in experimental animal models, as well as for mechanisms that regulate the flow of metabolic fuels and lead to the storage of fat.
Achievements in endocrinology and metabolism are applicable to many diseases because of the far-reaching effects of hormones and metabolic processes throughout the body. The Institute's research on the endocrinology and metabolism of bone is highly relevant to combating osteoporosis--a critical health problem of elderly women. NIDDK grantees have identified a number of growth factors that may play an influential role in the regulation of bone metabolism and the osteoporosis disease process. The Institute is
also generating knowledge about the mechanisms whereby the female hormone estrogen protects against bone resorption in osteoporosis.
Research on inherited metabolic diseases advanced this year with the approval by the FDA of a treatment for children whose immune systems are destroyed by the deficiency of a key enzyme, called ADA. The new enzyme replacement treatment involves chemically protecting the critical enzyme to keep it from breaking down rapidly after administration. This novel enzyme delivery system was used to treat the first child to receive experimental gene therapy, and NIH investigators now wait to determine whether the newly inserted gene will make a normal product. Clearly, this new formulation of an enzyme treatment will be a valuable adjunct to gene therapy research.
The NIDDK research mission is broad and complex, encompassing many costly chronic diseases; health problems of the young and the elderly; and diseases that particularly affect women and minorities. In highlighting some of our research advances, I hope I have conveyed the scientific momentum we feel as we pursue our mission into the 1990s. Mr. Chairman, the budget request for the NIDDK is $658,557,000. I will be pleased to answer any questions.
BIOGRAPHICAL SKETCH OF DR. PHILLIP GORDEN
December 22, 1934. Baldwyn, Mississippi. Married, two children.
Education: B.A., Vanderbilt University, Nashville, Tennessee, 1957; M.D., Vanderbilt University School of Medicine, Nashville, Tennessee, 1961.
Professional History: 1961-62, Intern, Yale University, New Haven,
Professional Organizations: American College of Physicians,
Honors, Awards: Alpha Omega Alpha Medical Fraternity, 1961.
Senator HARKIN. Thank you, Dr. Gorden.
I know that Senator Reid has some questions for you.
Senator REID. You are very kind, Mr. Chairman, in allowing me to appear out of order after you have been here all morning.
Dr. Gorden, last year the committee provided the urology program an additional $2.5 million to be directed toward research on interstitial cystitis. Can you tell me how you intend to direct these funds?
Dr. GORDEN. Yes, sir; at the present time we have a request for applications for new research project grants in this area, and in addition we are soliciting applications for the establishment of a data base or registry. Both of those programs, that is, this increased research project grant program and the registry or data base program, are well on their way, and will be inaugurated in the very near future.
Senator REID. Will these moneys be used this year?
Dr. GORDEN. They will be used this year with the possible exception of the data base/registry, which may be difficult to fund this fiscal year for technical reasons relating to timing of the review process. But if it is not this fiscal year, it will be done very early in the next fiscal year.
Senator REID. Doctor, how much of the money is designated for the interstitial cystitis register?
Dr. GORDEN. We do not have the proposals in, so I cannot be precise. But we estimate a figure of something in the range of about $650,000, which would include a data coordinating center and three proposed clinical centers that will actually support this data coordinating center with clinical studies. And that is our present estimation at this point.
Senator REID. And is this a sufficient amount, as far as you know?
Dr. GORDEN. We believe that it will be sufficient. It always has the possibility of flexibility in the future once we get this program started.
Senator REID. I have some other questions that I will submit to the panel in writing, Mr. Chairman.
I would acknowledge that I am going to visit your facility sometime early next month, I think on the eighth.
Dr. GORDEN. We would be very pleased, Senator Reid.