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determined that, while a general reduction in hypertension is beneficial in slowing the disease, a specific reduction in the blood pressure within the kidney is most effective in reducing the rate of KDDM progression. NIDDK grantees have also established that high blood glucose levels in poorly controlled diabetics may lead to enhanced water and sodium absorption in the ki ey. These scientists believe that the molecular build-up may contribute to the hypertension and renal hypertrophy that characterize KDDM. This finding, coupled with recent reports that diabetics who have a family history of hypertension may experience a genetic predisposition to KDDM, provides significant clues about the cause and possible methods of preventing this life-threatening kidney disease of diabetes mellitus in the future.

CYSTIC FIBROSIS RESEARCH ADVANCES

Question. In your opening statement you briefly mentioned some recent progress that has been made in cystic fibrosis research. What were some of the other significant advances made in this area during the past year, and what are the clinical implications of these findings?

Answer. It is indeed gratifying to the Institute to see that our broad support of cystic fibrosis research has produced some very exciting results. Other major advances in cystic fibrosis research this past year include reports by NIDDK grantees that direct correlations exist between CF gene defects and the clinical severity of CF, and that sophisticated techniques have been developed to visualize chloride transport, and defects thereof, under the microscope.

The continued expansion of fundamental knowledge about CF will hopefully lead to methods for bypassing the defective chloride ion channel regulation mechanism, to drugs that could alter the defective cystic fibrosis transmembrane regulator (CFTR) protein molecule, to gene therapy to replace the defective protein with a normal molecule, to improved diagnostic tests for the CF gene, and to techniques for replacing CFTR directly. We are confident that, ultimately, knowledge in these areas will translate into improved health for CF patients.

CYSTIC FIBROSIS RESEARCH EFFORTS

Question. We know the NIDDK is strongly committed to cystic fibrosis research, leading to an effective treatment, and hopefully the prevention, of this disease. What has your Institute done this past year to help progress toward these goals?

Answer. NIDDK and the Cystic Fibrosis Foundation jointly · issued a Request for Applications on the molecular basis of CF. The outstanding applications received in response to this solicitation will significantly expand the national research effort directed at CF. NIDDK also issued a "Cystic Fibrosis Core Center Grant" RFA in early 1990. NIDDK anticipated receipt of a competing continuation application from the existing Core Center, and invited other competing applications for a single Core Center grant to be awarded in Fiscal Year 1991. The existing Core Center at Case

Western Reserve Medical School was judged to be outstanding and will receive continued support.

The NIDDK supported a number of important conferences related to CF. The 1990 NIDDK "Fifth Annual Cystic fibrosis Lecture Series: Recent Developments and New Trends in the Study of Cystic Fibrosis" brought leaders in CF research to NIH for a stellar series of lectures. NIDDK organized a workshop on "Current Issues in Screening for Cystic Fibrosis." The purpose of this workshop was to formulate a scientific statement to guide the introduction of carrier testing for cystic fibrosis into general medical practice. The statement developed was published in the New England Journal of Medicine: The NIDDK and the Cystic Fibrosis Foundation cosponsored a workshop "Drug Needs for Cystic Fibrosis" held at NIH on May 2, 1990, to foster interaction between academia and industry in developing new pharmaceutical approaches to the treatment of CF.

The NIDDK and the Cystic Fibrosis Foundation jointly sponsor a fellowship program that provides training, at the NIH, for qualified physicians in research careers relevant to cystic fibrosis. This program focuses on molecular genetics, ultrastructure, biochemistry, pharmacology, embryology of ion channels, mucins, and secretory processes.

CYSTIC FIBROSIS REQUEST FOR APPLICATIONS

Question. Your Institute released a Request for Applications this past year for research on cystic fibrosis. What were the results of this RFA?

Answer. In an innovative joint effort, the NIDDK and the Cystic Fibrosis Foundation solicited investigator-initiated research grant applications to define and characterize the molecular pathophysiology of cystic fibrosis. With the ultimate goal of developing effective new therapy for the disorder, the solicitation was intended to capitalize on the recent identification of the CF gene, the cystic fibrosis transmembrane regulator (CFTR) protein encoded by this gene, and the major mutation responsible for the defective function of this protein in CF.

A total of 63 applications were received in response to the RFA of which the NIDDK intends to fund 13 at an approximate total cost of $2.1 million in FY 1991. The Cystic Fibrosis Foundation will provide more limited funding for a similar number of meritorious grants beyond those to be funded by NIDDK. The applications to be funded were of very high quality and should contribute substantially to progress in understanding and treating cystic fibrosis.

Question. Judging from the response to your latest RFA for CF, and the fact that you are unable to fund many scientifically meritorious applications, it appears we are not taking full advantage of this country's research potential in this area. What is your assessment, and what are some of the scientific opportunities in cystic fibrosis research?

Answer. In recent years we have vastly expanded our understanding of the pathogenesis of CF and at the same time improved the length and quality of life of patients afflicted with CF.

We need to expand on this progress to develop effective therapy targeted at the basic defect in CF. Both gene therapy and pharmacologic therapies offer promise in this regard. Several of our investigators, as well as a member of our National Advisory Council, have expressed interest in the establishment of gene therapy centers, in which cystic fibrosis research would be a cornertone. Because so much progress in CF has resulted from the application of advances in basic molecular and cell biology to understanding CF, I believe it is essential to provide adequate support for this basic research. Thus NIDDK is supporting research directly aimed at developing techniques for gene therapy in CF and also a broader array of projects to resolve obstacles to progress in gene therapy. Many questions remain about molecular mechanisms of normal and aberrant chloride transport characteristic of CF. Elucidation at the molecular level of the structure and function of elements of membrane transport systems offers the key to rational drug design targeted at the basic defect.

KIDNEY INITIATIVES AND ADVANCES

Question. Over 13 million Americans suffer from various kidney diseases and last year over 250,000 people died from kidney and related diseases. Kidney diseases are among the nation's most acute and growing public health problems. As a result the Congress encouraged the NIDDK to place a special priority on research initiatives investigation in the area of kidney and related diseases. Can you tell me what has been done in response to Congress' request? What is being done at improving the understanding and treatment of kidney diseases?

Answer. There have been NIDDK initiatives in the areas of End-Stage Renal Disease, Progression in Kidney Disease, and Basic Research in Kidney Disease. The initiative directed at the causes of dialysis morbidity and mortality is the newest activity. The initial work was the development of a database on which to develop the appropriate research strategies. This resource is called the United States Renal Data System. The second is to evaluate dialysis and transplantation technologies since the mortality rate for hemodialysis patients remains at nearly 20 percent annually, an unacceptably high rate. In addition, fewer than 60 percent of renal transplants are functioning five years after placement; and the patients must return to dialysis or receive another transplant. For these reasons, a five-year research research plan was developed which begins with a consensus meeting on dialysis therapy in FY 1992. This will be followed by a research solicitation.

A group of clinically relevant studies are directed at the intervention, or slowing, of renal disease progression to complete renal failure. Two studies are directed at the control of blood pressure in diabetics, and one addresses the efficacy of controlling dietary protein intake and blood pressure. A third group of clinical studies are the effect of the strict control of blood glucose on the development of kidney disease in juvenile

diabetics and the natural history of diabetes mellitus in the Native American population (Pima Indians).

Finally, we are pursuing an active basic research program into the causes and consequences of renal diseases, including polycystic kidney disease, kidney disease of diabetes mellitus, genetic kidney diseases, hypertension and kidney disease in minorities, and acute renal failure due to toxic or circulatory injuries.

RECOMMENDATION OF THE NATIONAL KIDNEY AND UROLOGIC DISEASES

ADVISORY BOARD

Question. Last year over 250,000 people died from kidney and related diseases. In your professional opinion, to increase funding for kidney disease funding, how much would be necessary? How would that money be spent ?

Answer. The National Kidney and Urologic Diseases Advisory Board recommended the following: (1) Increase NRSA funds by $8 million annually, (2) Increase Career Development Awards by $5 million annually, (3) Increase the Research Grant Budget by $46 million annually, (4) Increase the number of George O'Brien research centers to 18, costing $15 million annually, and (5) Increase the effort in clinical trials research, costing $20 million annually.

GEORGE O'BRIEN KIDNEY CENTERS

Question. The NIDDK currently supports six George O'Brien Kidney and Urology Research Centers. In 1991, the NIDDK established a multidisciplinary Research Center of Excellence in Pediatric Nephrology and Urology. At the current time do existing research opportunities warrant new centers, and if so, in what areas would the NIDDK focus research efforts on?

Answer. There is a major need to extend and expand research into the basic causes of prostate diseases. At the present time prostate diseases account for the most common causes of surgical intervention in adult males, and the incidence continues to increase as the population ages. Minority populations are at substantially increased risk for prostate diseases. For these reasons research on the basic aspects of prostate growth and function is imperative. There is now only one center dedicated to research on prostate diseases. In that center there have been several significant research advances made over its short three year history. These include the isolation of a factor in the fluid derived from the testis that promotes excess prostate growth, and the isolation of the cellular elements of the prostate and ability to grow them in culture so that further studies can be quickly · done. This demonstrates that the state of the basic science knowledge and expertise is now at a state that significant new advances can be made if new research centers on prostate were to be initiated. The American Urology Association has recognized this need, as well, and has this as its top priority for the next few years.

INFLAMMATORY BOWEL DISEASE

Question. Last year the Committee added $2,000,000 for research in inflammatory bowel disease--Crohn's disease and ulcerative colitis. What activities have been supported with this additional funding?

Inflammatory bowel disease (IBD) research has benefited greatly from the infusion of the funds which the Committee provided. With this assistance, the division was able to provide additional support to several of our Digestive Diseases Centers, which conduct IBD research. Among new research projects submitted during FY 1991, we were able to fund three outstanding grants. In addition, we were able to fund several investigators whose applications had received excellent priority scores but were not in the normal fundable range.

Is this an area of research that is "ripe" for further advances if funding were available?

Last year, the Institute issued a program announcement regarding IBD. The biomedical research community has responded by submitting over 28 research grant (R01) and program project grant (P01) applications to investigate the etiology and mechanisms of disease in IBD. It is clear from the wide range of topics (from the evaluation of animal models to the genetics of IBD) that many established investigators are willing to focus their research activities in this important area. Thus, intensified and funded research in this area should provide important answers to our understanding and treatment of IBD, which is estimated to affect two million Americans.

Question. Do you have ongoing contact with the Crohn's and Colitis Foundation of America (formerly the National Foundation for Ileitis and Colitis) so that research advances can be communicated to the patient population through newsletters, support groups, and educational programs sponsored by such voluntary health agencies?

Answer. Over the years, the Division of Digestive Diseases and Nutrition (DDDN) has been in the process of building a very cooperative relationship with the Crohn's and Colitis Foundation of America (CCF) (formerly with NFIC). In 1989, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) held a workshop on Inflammatory Bowel Disease (IBD) to discuss the future research agenda. The CCF was invited and many members of that organization presented information which has been used as a blueprint for program planning of the division. In addition, the NIDDK-supported National Digestive Diseases Information Clearinghouse provides a central point for the exchange of information among professional organizations, foundations, and voluntary health organizations involved with digestive diseases, including inflammatory bowel disease. A database of materials produced by voluntary and professional organizations, hospitals, manufacturers, government agencies, and a variety of other sources has been created and is available through the combined Health Information Database.

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