The NIH Almanac

Until May 19, 1972, the National Institute of Arthritis and Metabolic Diseases; until June 23, 1981, the National Institute of Arthritis, Metabolism, and Digestive Diseases; and until April 8, 1986, the National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases.

Mission

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) conducts and supports research on many of the most serious diseases affecting public health. The Institute supports much of the clinical research on the diseases of internal medicine and related subspecialty fields, as well as many basic science disciplines.

The Institute's Division of Intramural Research encompasses the broad spectrum of metabolic diseases such as diabetes, obesity, inborn errors of metabolism, endocrine disorders, mineral metabolism, digestive and liver diseases, nutrition, urology and renal disease, and hematology. Basic research studies include biochemistry, biophysics, nutrition, pathology, histochemistry, bioorganic chemistry, physical chemistry, chemical and molecular biology, and pharmacology.

NIDDK extramural research is organized into 4 divisions: Diabetes, Endocrinology, and Metabolic Diseases; Digestive Diseases and Nutrition; Kidney, Urologic, and Hematologic Diseases; and Extramural Activities.

The Institute supports basic and clinical research through investigator-initiated grants, program project and center grants, and career development and training awards. The Institute also supports research and development projects and large-scale clinical trials through contracts.

Important Events in NIDDK History

August 15, 1950—President Harry S. Truman signed the Omnibus Medical Research Act into law establishing the National Institute of Arthritis and Metabolic Diseases (NIAMD) in the U.S. Public Health Service. The new Institute incorporated the laboratories of the Experimental Biology and Medicine Institute and expanded to include clinical investigation in rheumatic diseases, diabetes, and a number of metabolic, endocrine, and gastrointestinal diseases.

November 15, 1950—The National Advisory Arthritis and Metabolic Diseases Council held its first meeting and recommended approval of NIAMD's first grants.

November 22, 1950—U.S. Surgeon General Leonard Scheele established NIAMD.

1959—Dr. Arthur Kornberg, former chief of the Institute's enzyme and metabolism section, won the Nobel Prize for synthesizing nucleic acid.

The Institute initiated an intramural research program in gastroenterology and launched an intramural research program in cystic fibrosis with the establishment of the Pediatric Metabolism Branch.

1961—Laboratory-equipped, mobile trailer units began an epidemiological study of arthritis among the Blackfeet and Pima Indians in Montana and Arizona, respectively.

October 16, 1969—The Nobel Prize was awarded to Dr. Marshall W. Nirenberg of the National Heart Institute, who reported his celebrated partial cracking of the genetic code while an NIAMD scientist (1957-1962).

November 1970—The Institute celebrated its 20th anniversary. U.S. Secretary of Defense Melvin R. Laird addressed leaders in the department, representatives from voluntary health agencies and professional biomedical associations, as well as past and present Institute National Advisory Council members.

May 19, 1972—The Institute name was changed to the National Institute of Arthritis, Metabolism, and Digestive Diseases.

October 1972—Christian B. Anfinsen, chief of the Institute's Laboratory of Chemical Biology, shared a Nobel Prize with 2 other American scientists for his demonstration of one of the most important simplifying concepts of molecular biology, that the 3-dimensional conformation of a native protein is determined by the chemistry of its amino acid sequence. A significant part of this research cited by the award was performed while with NIH.

September 1973—The Institute's diabetes centers program was initiated with the establishment of the first Diabetes-Endocrinology Research Centers.

November 1975—After 9 months of investigation into the epidemiology and nature of diabetes mellitus and public hearings throughout the United States, the National Commission on Diabetes delivered its report, the Long-Range Plan to Combat Diabetes, to Congress. Recommendations encompassed expansion and coordination of diabetes and related research programs; creation of a diabetes research and training centers program; acceleration of efforts in diabetes health care, education, and control programs; and establishment of a National Diabetes Advisory Board.

April 1976—After a year of study and public hearings, the National Commission on Arthritis and Related Musculoskeletal Diseases issued The Arthritis Plan—its report to Congress. The report called for increased arthritis research and training programs, multipurpose arthritis centers, epidemiologic studies and data systems in arthritis, a National Arthritis Information Service, and a National Arthritis Advisory Board.

October 1976—Dr. Baruch Blumberg was awarded the Nobel Prize in Physiology or Medicine for research on the hepatitis B virus protein, the "Australia antigen," which he discovered in 1963 while at the Institute. This advance has proven to be a scientific and clinical landmark in detection and control of viral hepatitis and led to the development of preventive measures against hepatitis and liver cancer.

April 19, 1977—The NIH Director established a trans-NIH program for diabetes, with lead responsibility in NIAMDD.

September 1977—Over $5 million in grants was awarded to 5 institutions to establish Diabetes Research and Training Centers.

October 1977—In response to the recommendation of the National Commission on Diabetes, the National Diabetes Data Group was established within the Institute to collect, analyze, and disseminate data on this disorder to scientific and public health policy and planning associations.

December 1977—Institute grantees Dr. Roger C.L. Guillemin and Dr. Andrew V. Shally shared the Nobel Prize in Physiology or Medicine with a third scientist, Dr. Rosalyn S. Yalow. Guillemin and Shally's prizes were for discoveries related to the brain's production of peptide hormones.

December 1978—A study of cystic fibrosis focused on the need for future research activities, including increased support for clinical and basic research, expansion of specialized cystic fibrosis research resources, emphasis on training of scientific personnel, and coordination of public and private cystic fibrosis research activities.

January 1979—Following 2 years of study and public hearings, the National Commission on Digestive Diseases issued its report, The National Long-Range Plan to Combat Digestive Diseases. Recommendations to Congress included the establishment of a National Digestive Diseases Advisory Board, an information clearinghouse, and increased emphasis on educational programs in digestive diseases in medical schools.

December 1979—A task force completed its study and submitted the report, An Evaluation of Research Needs in Endocrinology and Metabolic Diseases.

September 1980—Dr. Joseph E. Rall, director of NIAMDD intramural research, became the first person at NIH to be named to the distinguished executive rank in the Senior Executive Service. President Jimmy Carter presented the award in ceremonies at the White House on September 9.

October 15, 1980—NIAMDD celebrated its 30th anniversary with a symposium, "DNA, the Cell Nucleus, and Genetic Disease," and dinner at the National Naval Medical Center. Dr. Donald W. Seldin, chairman of the department of internal medicine, University of Texas Southwestern Medical School, Dallas, was guest speaker.

June 23, 1981—The Institute was renamed National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases.

April 1982—U.S. Department of Health and Human Services (HHS) Secretary Richard S. Schweiker elevated NIADDK's programs to division status, creating 5 extramural divisions and the Division of Intramural Research.

November 1982—Dr. Elizabeth Neufeld received a Lasker Foundation Award. She is cited, along with Dr. Roscoe E. Brady of NINCDS, for "significant and unique contributions to the fundamental understanding and diagnosis of a group of inherited diseases called mucopolysaccharide storage disorders (MPS)."

November 1984—Grants totaling more than $4 million were awarded to 6 institutions to establish Silvio O. Conte Digestive Disease Research Centers. The research centers investigate the underlying causes, diagnoses, treatments, and prevention of digestive diseases.

April 8, 1986—The Institute's Division of Arthritis, Musculoskeletal and Skin Diseases became the core of the new National Institute of Arthritis and Musculoskeletal and Skin Diseases. The NIADDK was renamed the National Institute of Diabetes and Digestive and Kidney Diseases.

June 3, 1986—The National Kidney and Urologic Diseases Advisory Board was established to formulate the long-range plan to combat kidney and urologic diseases.

August 1, 1987—Six institutions were funded to establish the George M. O'Brien Kidney and Urological Research Centers.

December 25, 1987—In response to congressional language on the FY 1988 appropriation for the NIDDK, the institute established a program of cystic fibrosis research centers.

September 16, 1990—NIDDK celebrated its 40th anniversary. Dr. Daniel E. Koshland, Jr., editor of Science, was guest speaker.

June, 1991—The NIDDK Advisory Council established the National Task Force on the Prevention and Treatment of Obesity to synthesize current science on the prevention and treatment of obesity and to develop statements about topics of clinical importance that are based on critical analyses of the literature.

September 30, 1992—Three Obesity/Nutrition Research Centers and an animal models core to breed genetically obese rats for obesity and diabetes research were established.

October 12, 1992—Drs. Edwin G. Krebs and Edmond H. Fischer were awarded the Nobel Prize in Physiology or Medicine for their work on "reversible protein phosphorylation." They have received grant support from NIDDK since 1955 and 1956, respectively.

October 30, 1992—In response to congressional language on the Institute's FY 1993 appropriation, the NIDDK initiated a program to establish gene therapy research centers with emphasis on cystic fibrosis.

November 1, 1993—The functions of the NIH Division of Nutrition Research Coordination, including those of the NIH Nutrition Coordinating Committee, were transferred to NIDDK.

October 10, 1994—Dr. Martin Rodbell and Dr. Alfred G. Gilman received the Nobel Prize in Physiology or Medicine for discovering G-proteins, a key component in the signaling system that regulates cellular activity. Dr. Rodbell discovered the signal transmission function of GTP while a researcher in the National Institute of Arthritis and Metabolic Diseases, now NIDDK.

June 22, 1997—Led by NIDDK, NIH and the U.S. Centers for Disease Control and Prevention (CDC) announce the National Diabetes Education Program (NDEP) at the American Diabetes Association annual meeting in Boston. The NDEP's goals are to reduce the rising prevalence of diabetes, the morbidity and mortality of the disease, and its complications.

June 2000—In an effort to reduce the disproportionate burden of many diseases in minority populations, NIDDK initiated an Office of Minority Health Research Coordination.

November 16, 2000—NIDDK celebrated its 50th Anniversary. Professional societies in 8 U.S. locations and Canada sponsored scientific symposia and hosted an NIDDK exhibit. "A New Century of Science. A New Era of Hope" was published to highlight research supported and conducted by NIDDK and concluded the year with a joint scientific symposium at the Society for Cell Biology's 40th Anniversary meeting in December.

June 13, 2003—To avoid confusion with the newly-established NIH Obesity Research Task Force, NIDDK changed the name of its National Task Force on Prevention and Treatment of Obesity, established in 1991, to the Clinical Obesity Research Panel (CORP).

June 2003—The Report on Progress and Opportunities: Special Statutory Funding for Type 1 Diabetes Research described recent achievements and major projects that address unmet research needs in type 1 diabetes. From fiscal year 1998 through fiscal year 2008, the special funding program provides a total of $1.14 billion in research funds to supplement other funds for type 1 diabetes research provided through the regular appropriations process.

NIDDK Legislative Chronology

December 11, 1947—Under section 202 of Public Law 78-410, the Experimental Biology and Medicine Institute was established.

August 15, 1950—P.L. 81-692, the Omnibus Medical Research Act, authorized establishment of NIAMDD to "... conduct researches relating to the cause, prevention, and methods of diagnosis and treatment of arthritis and rheumatism and other metabolic diseases, to assist and foster such researches and other activities by public and private agencies, and promote the coordination of all such researches, and to provide training in matters relating to such diseases...." Section 431 also authorized the U.S. Surgeon General to establish a national advisory council.

May 19, 1972—President Richard M. Nixon signed P.L. 92-305 to bring renewed emphasis to research in digestive diseases by changing the name of the Institute to NIAMDD and by designating a digestive diseases committee within the Institute's National Advisory Council.

August 29, 1972—The National Cooley's Anemia Control Act (PL 92-414) authorized research in the diagnosis, treatment, and prevention of this debilitating inherited disease, also known as thalassemia, occurring largely in populations of Mediterranean and Southeastern Asian origin.

July 23, 1974—P.L. 93-354, the National Diabetes Mellitus Research and Education Act, was signed. The National Commission on Diabetes, called for by this act, was chartered on September 17, 1974. Members were appointed by the Secretary of the U.S. Department of Health, Education and Welfare (HEW) . The Act called for centers for research and training in diabetes and establishment of an intergovernmental diabetes coordinating committee, including NIAMDD and 6 other NIH institutes.

January 1975—The National Arthritis Act of 1974 (P.L. 93-640) was signed into law to further research, education, and training in the field of the connective tissue diseases. The HEW Secretary appointed the mandated National Commission on Arthritis and Related Musculoskeletal Diseases, June 2. The Act required centers for research and training in arthritis and rheumatic diseases and the establishment of a data bank, as well as an overall plan to investigate the epidemiology, etiology, control, and prevention of these disorders.

October 1976—P.L. 94-562, the Arthritis, Diabetes, and Digestive Diseases Amendments of 1976, established the National Diabetes Advisory Board charged with advising Congress and the HEW Secretary on implementation of the "Long-Range Plan to Combat Diabetes," developed by the National Commission on Diabetes. The law also established the National Commission on Digestive Diseases to deal with many problems, including investigation into the incidence, duration, mortality rates, and social and economic impact of digestive diseases.

The National Arthritis Advisory Board, established by the same law, reviews and evaluates the implementation of the Arthritis Plan, formulated by the Arthritis Act of 1974. The board advises Congress, the HHS Secretary, and heads of Federal agencies with respect to the plan and other Federal programs relating to arthritis.

December 1980—Title II of the Health Programs Extension Act of 1980, P.L. 96-538, changed the Institute's name to the National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases. The Act also established the National Digestive Diseases Advisory Board. The law authorized the National Diabetes Information Clearinghouse, the Diabetes Data Group, and the National Digestive Diseases Information and Education Clearinghouse. In addition, it reauthorized advisory boards for arthritis and diabetes research.

November 20, 1985—The Health Research Extension Act of 1985, P.L. 99-158, changed the Institute name to the National Institute of Diabetes and Digestive and Kidney Diseases. The act also established the National Kidney and Urologic Diseases Advisory Board. The law gave parallel special authorities to all Institute operating divisions, including authorization of the National Kidney and Urologic Diseases Information Clearinghouse; National Kidney, Urologic, and Hematologic Diseases Coordinating Committee; National Kidney and Urologic Diseases Data System; National Digestive Diseases Data System; kidney and urologic diseases research centers; and digestive diseases research centers.

June 10, 1993—The NIH Revitalization Act of 1993, P.L. 103-43, established NIDDK as the lead institute in nutritional disorders and obesity, including the formation of a research and training centers program on nutritional disorders and obesity.

It also provided for the directors of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute on Aging, National Institute of Dental Research, and the NIDDK to expand and intensify programs with respect to research and related activities concerning osteoporosis, Paget's disease, and related bone disorders.

July 25, 1997—A House report accompanying H.R. 2264 and Senate report with S. 1061, FY 1998 appropriations bills for Labor/HHS/Education, urged NIH and NIDDK to establish a diabetes research working group to develop a comprehensive plan for NIH-funded diabetes research that would recommend future initiatives and directions. Dr. C. Ronald Kahn, diabetes research working group chairman, presented "Conquering Diabetes, A Strategic Plan for the 21st Century" to the Congress on March 23, 1999.

August 1997—The Balanced Budget Act of 1997 (P.L. 105-33) established a Special Statutory Funding Program for Type 1 Diabetes Research . The program provided $30 million per year for fiscal years 1998 through 2002. This funding program augmented regularly appropriated funds that HHS received for diabetes research through the Labor-HHS-Education Appropriations Committees. The NIDDK, through authority granted by the HHS Secretary, has a leadership role in planning, implementing, and evaluating the allocation of these funds.

October 17, 2000—The "Children's Health Act of 2000 (P.L. 106-310) amended the Public Health Service Act with respect to children's health.  Title IV, entitled "Reducing Burden of Diabetes Among Children and Youth," section 402, specified that NIH conduct long-term epidemiology studies, support regional clinical research centers, and provide a national prevention effort relative to type 1 diabetes.

December 2000—The Fiscal Year 2001 Consolidated Appropriations Act (P.L. 106-554) extended and augmented the Special Statutory Funding Program for Type 1 Diabetes Research in amount and time, allocating an additional $70 million for Fiscal Year 2001 (for a total of $100 million for Fiscal Year 2001), an additional $70 million for Fiscal Year 2002 (for a total of $100 million for Fiscal Year 2002), and $100 million for Fiscal Year 2003.

October 2002—NIH issued a detailed progress report, Conquering Diabetes: Highlights of Program Efforts, Research Advances, and Opportunities, on NIH-funded diabetes research. The report describes research achievements and initiatives since 1999, when the Diabetes Research Working Group published its 5-year plan. The Congressionally established Group made scientific recommendations in 5 areas of extraordinary research opportunity: the genetics of diabetes, autoimmunity and the beta cell, cell signaling and cell regulation, obesity, and clinical research and clinical trials. The Group also made recommendations regarding the microvascular and macrovascular complications of diabetes, the special populations most affected by diabetes, and resource and infrastructure needs to further diabetes research.

December 17, 2002—President Bush signed into law H.R. 5738, a bill that will increase and extend funding for the Special Diabetes Program (formerly P.L. 105-33). The bill provides $750 million for type 1 diabetes research over a period of 5 years (FY 04-FY 08).

December 2002—The Public Health Service Act Amendment for Diabetes (P.L. 107-360) extended and augmented the Special Statutory Funding Program for Type 1 Diabetes Research in time and amount, allocating $150 million per year for fiscal years 2004 through 2008.

December 8, 2003—The Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (P.L. 108-173).  Title VII, Subtitle D, Section 733 of this law, entitled "Payment for pancreatic islet cell investigational transplants for Medicare beneficiaries in clinical trials," specifies that the Secretary, acting through NIDDK, conduct a pancreatic islet transplantation clinical trial that includes Medicare beneficiaries, and that Medicare cover the routine costs, the transplantation, and appropriate related items and services for the Medicare beneficiaries enrolled in the trial.

October 25, 2004—The Pancreatic Islet Cell Transplantation Act of 2004(P.L. 108-362) amended the Public Health Service Act for the purposes of increasing the supply of pancreatic islet cells for research, and providing for better coordination of Federal efforts and information on islet cell transplantation.  A provision of this law specified that the annual reports prepared by the Diabetes Mellitus Interagency Coordinating Committee, which is led by the NIDDK, include an assessment of the Federal activities and programs related to pancreatic islet transplantation.

September 2004—The reports accompanying the FY 2005 Senate and House Labor, HHS, Education appropriations bills (reports 108-345 and 108-636, respectively) called on the NIH and HHS to establish a national commission on digestive diseases to review the burden of digestive diseases in the United States and develop a long-range research plan to address this burden. The NIH Director subsequently established the National Commission on Digestive Diseases, under NIDDK leadership, in August 2005. Commission activities included public meetings, review of a report by the Digestive Diseases Interagency Coordinating Committee on the burden of digestive diseases in the United States, and the development of a Long-Range Plan for Digestive Diseases Research.

Biographical Sketch of NIDDK Director Griffin P. Rodgers, M.D., M.A.C.P.

Dr. Griffin P. Rodgers was named Director of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)—one of the National Institutes of Health (NIH)—on April 1, 2007. He had served as NIDDK's Acting Director since March 2006 and had been the Institute's Deputy Director since January 2001. Dr. Rodgers also has been chief of the Molecular and Clinical Hematology Branch since 1998; the branch is now administratively managed by NIH's National Heart, Lung and Blood Institute.

Dr. Rodgers received his undergraduate, graduate, and medical degrees from Brown University in Providence, R.I. He performed his residency and chief residency in internal medicine at Barnes Hospital and the Washington University School of Medicine in St. Louis. His fellowship training in hematology/oncology was in a joint program of the NIH with George Washington University and the Washington Veterans Administration Medical Center. In addition to his medical and research training, he earned a master's degree in business administration, with a focus on the business of medicine, from Johns Hopkins University in 2005.

As a research investigator, Dr. Rodgers is widely recognized for his contributions to the development of the first effective—and now FDA approved—therapy for sickle cell anemia. He was a principal investigator in clinical trials to develop therapy for patients with sickle cell disease. He also performed basic research that focused on understanding the molecular basis of how certain drugs induce gamma-globin gene expression. He was honored for his research with numerous awards including the 1998 Richard and Hinda Rosenthal Foundation Award, the 2000 Arthur S. Fleming Award, the Legacy of Leadership Award in 2002, and a Mastership from the American College of Physicians in 2005.

Dr. Rodgers has been an invited professor at medical schools and hospitals in France, Italy, China, Japan, and Korea. He has been honored with many named lectureships at American medical centers and has published over 150 original research articles, reviews, and book chapters and has edited 4 books and monographs.

Dr. Rodgers served as Governor to the American College of Physicians for the U.S. Department of Health and Human Services from 1994 to 1997. He is a member of the American Society of Hematology, the American Society of Clinical Investigation, and the Association of American Physicians, among others. He is the chair of the Hematology Subspecialty Board and is a member of the American Board of Internal Medicine Board of Directors. He is board certified in Internal Medicine, in Emergency Medicine, and in Hematology.

NIDDK Directors

Name	In Office from	To
William Henry Sebrell, Jr.	August 15, 1950	October 1, 1950
Russell M. Wilder	March 6, 1951	June 30, 1953
Floyd S. Daft	October 1, 1953	May 3, 1962
G. Donald Whedon	November 23, 1962	September 30, 1981
Lester B. Salans	June 17, 1982	June 30, 1984
Mortimer B. Lipsett	January 7, 1985	September 4, 1986
Phillip Gorden	September 5, 1986	November 14, 1999
Allen M. Spiegel	November 15, 1999	March 3, 2006
Griffin P. Rodgers	April 1, 2007	present

Research Programs

Division of Intramural Research

The Division of Intramural Research conducts research and training within the Institute's laboratories and clinical facilities in Bethesda, Maryland, and at the Phoenix Epidemiology and Clinical Research Branch in Arizona.

The Division has 12 Branches and 10 Laboratories that cover a wide range of research areas. In addition, there is a section on veterinary sciences, a section on biological chemistry, the Office of Technology Transfer, the Office of Fellow Recruitment and Career Development, and an Administrative Management Branch.  Six core laboratories provide scientific support services to investigators.

The Intramural Branches engage in both basic and clinical research on diabetes, bone metabolism, endocrinology, obesity, hematology, digestive diseases, kidney diseases, kidney transplantation ,and genetics. Additionally, the Phoenix Branch develops and applies epidemiologic and genetic methods to the study of diabetes and obesity. The tenth branch addresses mathematical modeling of biological problems.

The Laboratories are engaged in fundamental research related to the Institute's mission in the fields of molecular biology, structural biology, chemistry, cell biology, pharmacology, chemical physics, biochemistry, neuroscience, developmental biology, and mathematical modeling of biological problems.

The Laboratory Animal Science section provides research animal support and collaboration for Institute research programs.  The 6 core laboratories provide services to interested NIDDK scientists in the areas of proteomics and mass spectrometry, microarray, chemical biology, mouse metabolism/transgenic support, biotechnological support, and knockout mice.

Division of Diabetes, Endocrinology and Metabolic Diseases

The DEMD supports research and research training related to diabetes mellitus, endocrinology, and metabolic diseases, including cystic fibrosis. In addition, the Division leads the administration of the Trans-NIH Diabetes Program and coordinates federally supported diabetes-related activities.

Diabetes Research Programs

The Adipocyte Biology Research Program encompasses research that addresses the development and physiology of the adipocyte cell. Specific areas of support include studies on the properties of transcription factors that regulate adipocyte differentiation; research on the consequences of insulin action on adipocyte physiology; and use of animal and tissue culture models to understand adipocyte biology.

The Autoimmunity/Viral Etiology of Type 1 Diabetes Research Program emphasizes support of investigator-initiated basic and clinical research relating to autoimmune endocrine diseases, including type 1 diabetes and autoimmune thyroid disease (AITD). Applications that address the etiology and pathogenesis of type 1 diabetes, immunology, and viral etiology of diabetes are included. Studies utilizing animal models to further our understanding of type 1 diabetes are of continuing interest to this program. Studies that emphasize autoimmune thyroid disease, including Graves' disease, Hashimoto's thyroiditis, and their complications, are included. Humanized animal models of AITD are also included.

The Behavioral/Prevention Research Program encompasses individual, family, and community-based strategies aimed at prevention of diabetes and its complications through lifestyle modifications, education, and other behavioral interventions. Particular emphasis is placed on development of culturally sensitive, lifestyle interventions to prevent or treat diabetes in diverse high-risk populations including African Americans, Hispanic Americans, and Native Americans. Specific areas of research include the link between behavior and physical health as it relates to diabetes and complications; approaches to improving health-related behaviors and to enhancing diabetes self-management; and other aspects of diabetes care.

The Beta Cell Therapy Research Program focuses on research to develop alternative cell or tissue sources, as well as an understanding of the basic mechanisms that support regeneration or neogenesis of pancreatic islets. This program supports research in the following areas:

• Developing methods to expand pancreatic islets or beta cells for transplantation
• Optimizing growth conditions for islet cell proliferation and differentiation
• Deriving pancreatic islets from stem/precursor cells
• Assessing alternative cell or tissue sources by transplantation
• Animal models of islet regeneration and neogenesis.

The Clinical Islet Transplantation Consortium develops and implements a program of single- and/or multi-center clinical studies, accompanied by mechanistic studies, in islet transplantation with or without accompanying kidney transplantation, for the treatment of type 1 diabetes.

The Clinical Research in Type 2 Diabetes Program will focus on patient-oriented research (i.e., clinical studies and small clinical trials) related to:

• Pharmacologic interventions and/or lifestyle interventions to prevent or treat type 2 diabetes, including studies relevant to new drug development
• Development of surrogate markers for use in clinical trials for the prevention or treatment of type 2 diabetes
• Cellular therapies for the treatment of type 2 diabetes
• Improving the care of patients with type 2 diabetes

The Complications of Diabetes Research Program encompasses basic and clinical research related to acute (e.g., ketoacidosis and hyperosmolar coma) and chronic complications of type 1 and type 2 diabetes. Chronic complications include the vascular complications of diabetes and the effects of diabetes on any organ system. Clinical studies supported under this program include strategies to prevent or treat the complications of diabetes. Supported basic research examines the molecular and cellular mechanisms by which hyperglycemia mediates its adverse effects and the interrelationships among the mechanisms potentially involved in the pathogenesis of complications, including increased polyol pathway flux, alterations of intracellular redox state, oxidative stress, glycation of structural and functional proteins, altered expression of growth factors, enhanced activity of PKC, impaired synthesis of nitric oxide and other vasoactive substances, and altered metabolism of fatty acids.

The Developmental Biology Research Program supports research related to developmental genetic screens for identifying mutations that affect the formation of tissue such as bone, adipose, endocrine pancreas, or pituitary. Specific areas of support also include signals, signaling pathway components, and transcriptional factors that regulate pattern formation in the embryo, or control the fate, specifications, proliferation, and differentiation of cells in the formation of tissues and organs.

The Diabetes Centers Program administers 2 types of center awards, the Diabetes Endocrinology Research Centers (DERC) and the Diabetes Research and Training Centers (DRTC). An existing base of high-quality diabetes-related research is a primary requirement for establishment of either type of center. While not directly funding major research projects, both types of center grants provide core resources to integrate, coordinate, and foster the interdisciplinary cooperation of a group of established investigators conducting research in diabetes and related areas of endocrinology and metabolism. The 2 types of centers differ in that the DERC focuses entirely on biomedical research, while the DRTC has an added component in training and translation.

The Diabetes Mellitus Interagency Coordinating Committee (DMICC), established in 1974 and chaired by the DEMD Director, includes representatives from all Federal departments and agencies whose programs involve health functions and responsibilities relevant to diabetes mellitus and its complications. Functions of the DMICC include coordinating the research activities of NIH and those activities of other Federal programs that are related to diabetes mellitus and its complications;  ensuring the adequacy and soundness of these activities; and providing a forum for communication and exchange of information necessary to maintain coordination of these activities.

The Drug Discovery Program supports:

• Interdisciplinary activities and resources that increase understanding of physiological and pathophysiological processes relevant to therapeutic development in diabetes, endocrine, and metabolic disorders
• Research that seeks to elucidate molecular structures or biological pathways that may lead to the identification and validation of targets that can be potentially manipulated by ligands/inhibitors. “Druggable” molecular targets/pathways
• Studies of the potential bioavailability of compounds, the ability to modulate selectively the function of drug discovery targets, and the ability to translate biological endpoints of preclinical research to the clinic showing high potential for success in later stage drug development
• Development of high-throughput assays based on biologic pathways likely involved in the pathogenesis of diabetes and its complications that could be used to screen molecular libraries for novel therapeutic agents
• Research that seeks to discover new mechanisms of action for therapeutics used for diabetes, endocrine, and metabolic disorders, and the development and validation of disease models to evaluate novel therapeutics for these disorders.

The Endocrine Pancreas Research Program includes projects to elucidate the basic biology of the endocrine cells of the pancreas, which include alpha, beta, and delta cells within the islet. These include insulin or other hormone synthesis and secretion,;coupling of nutrient sensing to insulin secretion; cell interactions; role of incretins, cytokines, other hormones, and enervation; studies of apoptosis and cell turnover in the adult organ; metabolism, basic signal transduction, and regulation of gene transcription, especially as these areas relate to beta cell and islet function. This program also contains studies in cell culture to bioengineer glucose-responsive hormone-secreting cells or islets for eventual treatment of diabetes.

The Environmental Determinants of Diabetes in the Young (TEDDY) Program is a multi-center, multi-national, epidemiological study to identify infectious agents, dietary factors, or other environmental exposures that are associated with increased risk of autoimmunity and type 1 diabetes.

The Genetics of Type 1 Diabetes Research Program seeks to identify the genes that predispose to the development of type 1 diabetes and studies to determine their mechanism. Specific areas of support include:

• Studies of animal models of type 1 diabetes such as the NOD mouse and the BB rat to identify genes responsible for the development of type 1 diabetes
• Studies of the HLA region that contains the major genetic determinant for type 1 diabetes to understand its contribution to the development of diabetes
• Studies of immune regulatory regions that may contribute to both type 1 diabetes as well as other autoimmune disorders
• Development of genetic resources and patient samples for studies of type 1 diabetes
• Creation of animal models for therapeutic trials

The Genetics of Type 2 Diabetes Research Program seeks to identify genes that contribute to the development of type 2 diabetes mellitus. Specific areas of support include using animal models to identify diabetes genes; studies using quantitative statistical methods to identify diabetes genes in human populations; and development of genetic resources, patient samples, and methods for studying genetic linkage for diabetes.

The Glucose Sensors Research Program will contain projects aimed at developing or implementing glucose sensors that can determine glucose concentration in the plasma, interstitial fluid, or other appropriate space in diabetic patients continuously or in repeated samples. This program also includes development of the necessary components of glucose sensors (such as biocompatible materials or fluorescent glucose ligands, new sampling systems, etc.), software, mathematical algorithms and circuitry designed for calibration or insulin pump control, and devices that combine these sensors with insulin delivery systems in a ”closed-loop” artificial pancreas.

The Hypoglycemia in Diabetes Research Program encompasses clinical and basic studies on the pathogenesis, prevention, treatment, and sequelae (including hypoglycemia unawareness) of hypoglycemia in both type 1 and type 2 diabetes. Specific areas of research include studies to identify the neuronal and hormonal systems involved in recognition and response to hypoglycemia; examine the interplay of counterregulatory endocrine responses; and ascertain the regulatory mechanisms for glucose homeostasis and the cells involved in this regulation.

The Insulin Receptor/Structure/Function/Action Research Program encompasses studies of the structure, function, and action of the insulin receptor. Specific areas of support include:

• Molecular analysis of ligand binding to receptor
• Activation of the tyrosine kinase
• Subsequent insulin receptor function in signal transduction by serving as a platform for the attachment of downstream signaling molecules involved in insulin action
• Insulin Receptor Signaling proteins (IRS)-1,2,3,4, and other proteins containing Src Homology Domains (e.g., SH2)

The Islet Transplantation Research Program encompasses studies of therapeutic or preclinical approaches to treat diabetes. Specific areas include: Transplantation of pancreas, pancreatic endocrine cells (islets or beta cells), beta cells in culture or other insulin-producing cells in humans or animal models (including procedures to enhance tolerance, encapsulate/immunoisolate islets or other means to improve transplant survival). The program also includes gene therapy or other approaches to manipulate islets to improve viability, durability, or other aspects of transplantation.

The Molecular and Functional Imaging Program comprises projects that employ novel molecular and functional imaging techniques to visualize various aspects of diabetes and obesity, endocrinology, metabolism, and metabolic diseases. The emphasis will be on in vivo techniques (PET, MRI, Ultrasound, CT, optical tomography, etc.), with applications serving to tag tissues and cells of interest; study biological processes in vivo; diagnose disease; or monitor progress during therapy. These will be studies either to monitor physiological or metabolic processes, rate of metabolism, blood flow, sites of hormone action, etc., using imaging and spectroscopic techniques or to identify cell types using molecular imaging probes. Another application might be the technology to develop a probe to identify in vivo the sites within the hypothalamus that control satiety.

The Mouse Metabolic Phenotyping Program contains a consortium of centers with the purpose of phenotyping mouse models of diabetes and its complications, obesity, or other chronic metabolic diseases. It will include the development of new tests for phenotyping mice, adaptation or miniaturization of existing tests, as well as the performance of these tests to more fully characterize new or existing models of disease. Emphasis is placed on noninvasive or minimally invasive technologies that can be used for longitudinal studies, but this program also includes high-throughput metabolic screens. Examples include glucose and insulin clamps; miniaturized assays for hormones, cytokines, nutrients, or intermediary metabolites; kinetic measures of metabolic processes; immunological parameter; measurements of energy balance, body composition, and activity; measures for metabolic, behavioral, and physiologic abnormalities during disease progression.

The National Diabetes Data Group (NDDG) serves as the major Federal focus for the collection, analysis, and dissemination of data on diabetes and its complications. Drawing on the expertise of the research, medical, and lay communities, the NDDG initiates efforts to:

• Define the data needed to address the scientific and public health issues in diabetes
• Foster and coordinate the collection of these data from multiple sources
• Identify important data sources on diabetes, and analyze and promulgate the results of these analyses to the scientific and lay public
• Promote the timely availability of reliable data to scientific, medical, and public organizations and individuals
• Modify data reporting systems to identify and categorize more appropriately the medical and socioeconomic impact of diabetes
• Promote the standardization of data collection and terminology in clinical and epidemiologic research
• Stimulate development of new investigator-initiated research programs in diabetes epidemiology.

The National Diabetes Education Program (NDEP), co-sponsored by the NIDDK and the CDC, is focused on improving the treatment and outcomes for people with diabetes, promoting early diagnosis, and ultimately preventing the onset of diabetes. The goal of the program is to reduce the morbidity and mortality associated with diabetes through public awareness and education activities targeted to the general public, especially those with at risk for type 2 diabetes, people with diabetes and their families, health care providers, and policy makers and payers. These activities are designed to:

• Increase public awareness that diabetes is a serious, common, costly, and controllable disease that has recognizable symptoms and risk factors
• Encourage people with diabetes, their families, and their social support systems to take diabetes seriously and to improve practice of self-management behaviors
• Reduce disparities in health care in racial and ethnic populations disproportionately affected by diabetes
• Alert health care providers to the seriousness of diabetes, effective strategies for its control, and the importance of a team care approach to helping patients manage the disease. Toward these ends, the NDEP is developing partnerships with organizations concerned about diabetes and the health care of its constituents.

The Prevention of Type 1 Diabetes Research Program includes studies on drug development and cellular therapy that are being proposed to prevent type 1 diabetes. Areas of particular interest are:

• Studies on drug development for type 1 diabetes treatment or prevention
• Studies including the creation of animal models for therapy trials or humans to maintain normal blood glucose levels
• Tolerance induction for prevention of type 1 diabetes
• Immune intervention
• "Humanized" mouse model (development of transgenic NOD with human HLA molecules on the T cells) for type 1 diabetes
• Development of therapies for prevention of Impaired Glucose Tolerance (IGT) or interventions to prevent conversion of IGT to type 1 diabetes
• Drugs designed to enhance peripheral glucose metabolism or reduce hepatic glucose production of type 1 diabetics
• Therapies designed to increase insulin sensitivity of type 1 diabetics.

The Type 1 Diabetes Clinical Trials Program supports large, multi-center clinical trials conducted under cooperative agreements or contracts. One primary prevention trial has concluded. The Diabetes Prevention Trial Type 1 (DPT-1) was aimed at determining whether it was possible to prevent or delay the onset of type 1 diabetes in individuals determined to be at immunologic, genetic, and/or metabolic risk. It also supported future clinical trials of the Type 1 Diabetes TrialNet, which will conduct intervention studies to prevent or slow the progress of type 1 diabetes, and natural history and genetics studies in populations screened for or enrolled in these studies. The program also supports the Epidemiology of Diabetes Interventions and Complications (EDIC) study, an epidemiologic follow-up study of the subjects previously enrolled in the Diabetes Control and Complications Trial (DCCT).

The Type 2 Diabetes Clinical Trials Program supports large, multi-center clinical trials conducted under cooperative agreements or contracts. One primary prevention trial is underway. The Diabetes Prevention Program (DPP) is focused on testing lifestyle and pharmacological intervention strategies in individuals at genetic and metabolic risk for developing type 2 diabetes to prevent or delay the onset of this disease.

The Type 2 Diabetes in the Pediatric Population Research Program encompasses research on the pathophysiology, prevention, and treatment of type 2 diabetes in children. Specific areas of support include studies:

• To describe the epidemiology (incidence, prevalence, risk factors) of type 2 diabetes and its complications in children
• To develop diagnostic criteria to distinguish type 1 and type 2 diabetes in children
• To define the metabolic abnormalities (and the natural history of such abnormalities) in children with type 2 diabetes
• To develop practical, effective strategies for the prevention and/or treatment of type 2 diabetes in children
• To understand the basis for race/ethnic disparities in the incidence of type 2 diabetes in the pediatric population.

Endocrinology Research Programs

The Bone and Mineral Metabolism Research Program encompasses basic and clinical research on the hormonal regulation of bone and mineral metabolism in health and disease. Specific areas of support include:

• Endocrine aspects of disorders affecting bone, including osteoporosis, Paget's disease, renal osteodystrophy, and hypercalcemia of malignancy
• Pathogenesis, diagnosis, and therapy of parathyroid disorders, including primary or secondary hyperparathyroidism;
• Effects of parathyroid hormone, parathyroid hormone-related protein, calcitonin, vitamin D, estrogen, retinoic acid, growth factors (e.g., IGF-I), glucocorticoids, thyroid hormone, and other systemic or local-acting hormones and their receptors on bone metabolism
• Bone active cytokines (e.g., TGF-b, BMPs, CSF-1)
• Studies of calcium homeostasis, absorption, metabolism, and excretion, including the calcium-activated receptor
• Basic and clinical studies of vitamin D
• Bone morphogenesis, including the roles of developmental factors in bone formation (e.g., hedgehogs, Hox genes)

The G-Protein Coupled Receptors Program encompasses studies on the G-protein coupled receptor superfamily. Specific areas of support include:

• Cell surface, or 7-transmembrane domain, receptors coupled to GTP-binding ("G")- proteins for signal transduction (e.g., beta-adrenergic receptor)
• Receptor structure
• Receptor down-regulation (homologous desensitization)
• Role(s) of mutated receptors in disease
• Coupling of signaling through the receptor to other membrane-bound effectors and or regulators, such as adenylyl cyclase, ion channels, protein phosphatases or kinases, and other receptors.

Signal transduction through GPCRs also includes mechanisms of regulation of gene expression through nuclear proteins such as the Cyclic Nucleotide Response Element Binding Protein (CREB) and the CREB-binding protein.

The Integrative Biology of Obesity Program supports both basic and clinical research investigating the neural and endocrine mechanisms contributing to obesity and the pathophysiological consequences of obesity, particularly type 2 diabetes. Also included are studies that explore the neuronal and peptidergic pathways regulating food intake and other behaviors influencing body adiposity. Thus, proposals encompassed by this program will take an integrative approach to the goal of elucidating the physiological and behavioral factors contributing to the etiology of obesity. Clinical studies that expand on basic research findings and/or explore basic mechanisms involved in human obesity are encouraged. Examples of areas of interest include: Neurobiology of human obesity and behavior, neuropeptides and their receptors involved in the regulatory pathways controlling feeding behavior, satiety and energy expenditure, intrauterine and neonatal environment in the development of obesity, and imaging of neural pathways involved in the regulation of food intake.

The Intracellular Signal Transduction Research Program encompasses research aimed at understanding the structure and function of intracellular signal-transducing molecules. Specific areas of support include:

• Intracellular kinases, phosphatases, and anchoring proteins
• Signaling mechanisms that have altered activity in response to protein phosphorylation, calcium, and cAMP
• Approaches to solving the 3-dimensional structure of signaling proteins including crystallography and NMR
• Functional analysis of these proteins, including comparison of wild-type and naturally occurring or synthetic, mutant proteins, or expression of dominant-negative forms of the proteins
• Microscopic techniques to localize these proteins within cells
• Identification of substrates for these signaling proteins
• Analysis of crosstalk among distinct signal transduction pathways

The Neuroendocrinology Research Program encompasses research on neuropeptides of the hypothalamus. Specific areas of research support include:

• Physiological response to stress through the hypothalamic-pituitary-adrenal axis
• Neuropeptides and neuropeptide receptor signaling pathways
• Gene regulation in the hypothalamus and pituitary gland
• Diseases of the pituitary including neoplasia
• Hypopituitary dwarfism
• Identification and characterization of novel hypothalamic or pituitary hormones
• Tissue-specific and developmental expression of pituitary and hypothalamic genes
• Pituitary hormone receptors and actions on target tissues (e.g., GH IGF-1 axis)
• Neuropeptide receptors in diagnosis and treatment of disease
• Neuroendocrine-immune interactions

The Nuclear Receptor Superfamily Program encompasses basic and clinical research on members of the steroid hormone superfamily (also known as the nuclear receptor superfamily). The program includes structure/function studies and the role in signal transduction and regulation of gene expression of:

• Steroid hormones, including glucocorticoids, mineralocorticoids, progesterone, estrogens, androgens (testosterone), and DHEA
• Nuclear receptors, including thyroid hormone, vitamin D, retinoids (RAR, RXR, vitamin A), PPARs, and orphan receptors (LXR, Nur77, COUP-TF, and others).

Topics covered include receptor structure, interaction with cytoplasmic chaperones (e.g., Hsp90, Hsp70, etc.), interaction with ligand, nuclear translocation, binding to hormone response elements, interaction with nuclear accessory proteins (e.g., SRC-1, N-CoR, CBP, histone acetylase/deacetylase, GRIP1, etc.), and regulation of gene expression.

The Regulation of Energy Balance and Body Composition Research Program encompasses research on regulation of body composition by the hypothalamus and circulating factors. Specific areas of support include:

• Endocrinology of body composition, including interactions between nutrition, exercise, and anabolic hormones
• Neuropeptides and their receptors involved in regulatory pathways controlling feeding behavior, satiety, and energy expenditure
• Interactions between hypothalamicpituitary adrenal axis and peripheral metabolic signals (e.g., insulin), leptin, and glucocorticoids
• Hormones and cytokines involved in wasting syndromes (e.g., cancer, AIDS)
• Endocrine regulation of energy balance via uncoupling proteins
• Hypothalamic integration of peripheral endocrine and metabolic signals

Metabolic Diseases Research Programs

The Functional Metabolomics Program includes grants focused on the application of technology used to measure large-scale integrated metabolism of cells, tissues, and organ system. These studies can be done in vivo, in isolated tissue, or in cell culture. They have a focus on applying novel technology advancements in measuring and identifying many metabolites within multiple pathways. Emphasis is on discovering new, potentially mechanistic relationships between changes in metabolite profile and the etiology or pathology of specific metabolic diseases or syndromes that fall within NIDDK’s scope of research. Important goals include in vivo and translational potential of technology to rapidly analyze and interpret large networks of pathways and fluxes to gain a more complete view of metabolome dynamics.

The Gene Therapy and Cystic Fibrosis Centers Program supports 3 types of centers: Gene Therapy Centers (P30), Cystic Fibrosis Research Centers (P30), and Specialized Centers for Cystic Fibrosis Research (P50). Gene Therapy Centers provide shared resources to a group of investigators to facilitate development of gene therapy techniques and to foster multidisciplinary collaboration in the development of clinical trials for the treatment of cystic fibrosis and other genetic metabolic diseases. Cystic Fibrosis Research Centers and Specialized Centers for Cystic Fibrosis Research provide resources and support research on many aspects of the pathogenesis and treatment of cystic fibrosis.

The Cystic Fibrosis Research Program supports investigator-initiated research grants encompassing both fundamental and clinical studies of the etiology, molecular pathogenesis, pathophysiology, diagnosis, and treatment of cystic fibrosis and its complications. Particular areas of emphasis of the program include:

• Characterization of the cystic fibrosis gene, its mutations, and the molecular mechanisms by which mutations cause dysfunction
• Studies of the cystic fibrosis transmembrane regulator (CFTR) protein encoded by the cystic fibrosis gene, including its processing, trafficking, and folding, and the mechanisms by which mutations alter CFTR trafficking and structure/function
• Elucidation of the pathways of electrolyte transport in affected epithelia and the relationship between CFTR and other epithelial ion channels
• Elucidation of the potential roles of CFTR in the transport of molecules other than chloride, posttranslational processing of mucins and other proteins, exocytosis and recycling of cell membranes, subcellular organelle function, and other cellular processes
• Studies of the relationship between genotype and phenotype in cystic fibrosis and identification of genetic or environmental factors that explain the variable clinical presentations and severity of disease
• Delineation of the mechanisms underlying the inflammation and infection characteristic of cystic fibrosis. Analysis of how mutations in the cystic fibrosis gene and alterations in CFTR function result in inflammation and infection
• Research on other clinical manifestations of cystic fibrosis, including the pathophysiologic mechanisms underlying malnutrition and growth failure, impaired fertility, liver disease, and overall physical and psychosocial development. Investigation of approaches to ameliorate the complications of cystic fibrosis
• Development of potential therapeutic approaches to modulating the transport defect in cystic fibrosis and to stabilize mutant CFTR and enhance its targeting and integration into the cell membrane
• Development of safe and effective methods for gene therapy
• Development of animal or cell models useful for studying cystic fibrosis and its therapy
• Evaluation of therapeutic interventions in cystic fibrosis in clinical studies or animal models

The Gene Therapy Research Program encompasses research aimed at developing basic and applied gene therapy for genetic metabolic diseases. Specific areas of support include:

• Pilot and feasibility studies (R21) to improve gene delivery systems
• Studies of the basic science of AAV, adenovirus, retrovirus, and lentivirus vectors
• Studies of non-viral methods of gene transfer such as liposomes or DNA-conjugates
• Studies to target gene delivery to specific cell types
• Gene therapy of stem cells to treat a genetic metabolic disease

The Genomic Resource and Technology Development Program supports projects that take advantage of recent development in genetic analysis, genomic-based technologies, and systems biology to propose innovative ways of understanding the biological networks behind diseases of interest to NIDDK, such as metabolic disease. Emphasis will be put on assembling a community of researchers to propose integrated approaches and develop new tools to solve complex problems that are difficult to tackle in a traditional laboratory setting and that require multi-disciplinary teams. Areas of interest include:

• Genome-wide analysis of transcriptional regulatory networks in health and disease
• Tissue development and regeneration
• Functional genomics in disease-relevant organs under normal and pathological conditions
• Forward and reverse chemical genetics to explore regulatory networks involved in disease biology
• Development of high-throughput, cell-based screening platforms to interrogate basic and disease biology
• Development of partnerships and integrated research projects between physicians, geneticists, computational scientists, biochemists, and others, to better identify the underlying causes of complex diseases

The Inborn Errors of Metabolism Research Program encompasses research in the pathophysiology and treatment of genetic metabolic diseases. Specific areas of support include:

• Studies of etiology, pathogenesis, prevention, diagnosis, pathophysiology, and treatment of these diseases
• Characterization of the genes, gene defects, and regulatory alterations that are the underlying causes of these diseases
• Studies of the mutant enzyme and its effect on the structure and function of the protein
• Development of animal models for genetic disease
• Development and testing of dietary, pharmacologic, and enzyme replacement therapies
• Development of stem cell transplantation both prenatally and postnatally as a treatment for metabolic diseases

The Integrative Metabolism and Insulin Resistance Program comprises grants that study intermediary metabolism and physiology on the whole-body, organ, and cell level. These studies can be done in vivo, in isolated tissues, or in cell culture. They focus on flux and regulation of either a single metabolic pathway, interacting pathways in a cell or organ, or interactions between organs in the whole body. Especially important are in vivo measurements of whole-body flux, such as glucose production or turnover, or blood flow. Examples of important goals for these studies include an understanding of insulin resistance, regulation of gluconeogenesis and glucose disposal, protein turnover rate and regulation, cellular and whole-body lipid fluxes, interaction between carbohydrate and lipid metabolism, rate of tricarboxylic acid cycle flux and energy production in the cell, transcriptional regulation of important flux regulating enzymes or transporters for a given pathway, etc.

The Metabolomics Technology Development Roadmap Program promotes development of novel technologies to study cellular metabolites, such as lipids, carbohydrates, and amino acids. Knowledge gained from these studies will be used to understand more precisely the role of metabolites in the context of cellular pathways and networks.

The Protein Trafficking/Secretion/Processing Research Program encompasses research aimed at understanding the mechanisms that account for the fate of proteins after their initial translation. Specific areas of support include:

• Protein folding
• Post-translational modifications and the enzymes that catalyze them
• Movement of proteins in vesicles from the endoplasmic reticulum through the Golgi and endosomes and their ultimate secretion
• Mechanisms that account for vesicle formation (pinching off) and vesicle fusion, which are paramount to understanding trafficking
• Movement of proteins in the direction opposite of secretion, including endocytosis and retrograde transport
• Proteins and small molecules that regulate protein trafficking
• Proteasomes, ubiquitin conjugation, and the N-end rule

The Proteomics in Diabetes, Endocrinology, and Metabolic Diseases Program comprises grants that study the structure, mechanism, kinetics, and regulation of isolated purified proteins. This would include x-ray crystallography, mass spectroscopy, electron microscopy, nuclear magnetic resonance, and mutational studies of structure. It also includes studies of subunit interactions and interactions with small regulatory ligands, substrates, intermediates, and products. Of special interest are new technologies for structure determination (especially membrane proteins), crystallization, identification of interacting molecules and proteins, and assignment of function to unknown gene products of interest to the fields of diabetes, endocrinology, and metabolic diseases. High-throughput methods are highlighted. All informatics associated with the field of proteomics are included.

Division of Digestive Diseases and Nutrition

This Division supports research related to liver and biliary diseases; pancreatic diseases; gastrointestinal diseases, including neuroendocrinology, motility, immunology, and digestion in the GI tract; nutrient metabolism; obesity; eating disorders; and energy regulation. The Division provides leadership in coordinating activities related to digestive diseases and nutrition throughout the NIH and with various other Federal agencies.

Gastrointestinal Disease Programs

Investigators supported by the Gastrointestinal Motility Program focus their research on the structure of gastrointestinal muscles, the biochemistry of contractile processes and mechanochemical energy conversion relations between metabolism and contractility in smooth muscle, the extrinsic control of digestive tract motility, and the fluid mechanics of gastrointestinal flow. Other studies and areas of interest include the actions of drugs on gastrointestinal motility; intestinal obstruction; and diseases such as irritable bowel syndrome (functional digestive disorders), colonic diverticular disease, swallowing disorders, and gastroesophageal reflux.

The research emphasis of the Gastrointestinal Mucosa and Immunology Program focuses on intestinal immunity and inflammation. Areas of interest include ontogeny and differentiation of gut-associated lymphoid tissue; migratory pathways of intestinal lymphoid cells; humoral antibody responses; cell-mediated cytotoxic reactions and the role of cytotoxic effector cells in chronic intestinal inflammation; genetic control of the immune response at the mucosal surface; immune response to enteric antigens in both intestinal and extra-intestinal sites; granulomatous inflammation; lymphokines and cellular immune regulation; leukotriene/prostaglandin effects on intestinal immune responses; T-cell mediated intestinal cell injury; the intestinal mast cell and its role in intestinal inflammation; approaches to optimal mucosal immunoprophylaxis, including viral, bacterial, and parasitic diseases; diseases such as gluten-sensitive enteropathy, inflammatory bowel disease, and gastritis; malabsorption syndromes; diarrhea; gastric and duodenal ulcers; disease of the salivary glands (excluding cystic fibrosis); the effects of prostaglandins and other treatment modalities on the gastrointestinal tract; and the possible role of prostaglandins or other agents in the pathogenesis and treatment of digestive diseases.

The Gastrointestinal Neuroendocrinology Research Program supports basic and clinical studies on normal and abnormal function of both the enteric nervous system and the elements within the central nervous system that control the enteric nervous system. Neuroendocrine studies include histochemical and neurochemical analyses of the enteric nervous system, electrical properties of enteric ganglia, chemical neurotransmission, neural control of effector function, and extrinsic nervous input. This program places emphasis on gastrointestinal hormones and peptides, including their structure, biological actions, structure-activity relationships, receptors, distribution, quantitation, metabolism, release, correlation with physiological events, deficiency, and the role of time variation in the data collected in the above studies. In addition, the program supports studies on disease conditions associated with excessive or inadequate secretion of neuropeptides.

The Gastrointestinal Transport and Absorption Program supports research on the process of food digestion, and absorption and transport in the gastrointestinal tract, including the synthesis and assembly of digestive enzymes; the transport of water, ions, sugars, amino acids, peptides, lipids, vitamins, and macromolecules; and the formation, structure, and function of chylomicrons. Other areas of research focus on the regulation of gene expression in the gastrointestinal tract; the structure and function of the gut mucosa; the cytoskeletal structure and contractility in brush borders; the growth and differentiation of gastrointestinal cells in normal and disease states; intestinal transplantation, storage, and preservation; and gastrointestinal tissue injury, repair, and regeneration. Also supported are studies on gastrointestinal diseases such as maldigestion and malabsorption syndromes.

The Acquired Immunodeficiency Syndrome Program encourages research into the characterization of intestinal injury, mechanism of maldigestion, and intestinal mucosal functions, as well as hepatic and biliary dysfunction in AIDS. In addition, studies are supported on mechanisms of nutrient dysfunction, deficiencies of various micronutrients nutritional management of the wasting syndrome and other aspects of malnutrition related to AIDS.

The Clinical Trials in Digestive Diseases Program supports patient-oriented clinical research focusing on digestive diseases. Small clinical studies (pilot), planning grants or phase III clinical trials may be appropriate to this program. The small clinical studies should focus on research that is innovative and/or potentially of high impact. They should lead to full scale clinical trials. Please see the current program announcement for small grants for clinical trials. Phase III clinical trials usually are multi-center and involve several hundred human subjects that are randomized to 2 or more treatments, 1 of which is usually a placebo. The aim of the trial is to provide evidence for support of, or a change in, health policy or standard of care. The interventions/treatments may include pharmacologic, nonpharmacologic, and behavioral interventions given for disease prevention, prophylaxis, diagnosis, or therapy. Areas of emphasis include: Helicobacter pylori; inflammatory bowel disease; functional bowel syndrome and constipation; non-ulcer dyspepsia; celiac disease; intestinal failure, short-gut syndrome, and small bowel transplantation.

The Digestive Diseases Research Core Centers Program provides a mechanism for funding shared resources (core facilities) that serve to integrate, coordinate, and foster interdisciplinary cooperation between groups of established investigators who conduct programs of high quality research that are related to a common theme in digestive disease research. An existing base of high-quality digestive disease-related research is a prerequisite for the establishment of a center. The research emphases of centers in this program presently focus on liver diseases, gastrointestinal motility, absorption and secretion processes, inflammatory bowel disease, structure/function relationships in the gastrointestinal tract, neuropeptides and gut hormones, and gastrointestinal membrane receptors. Due to a restriction on the number of core center grants that can be supported, new center grant proposals will be accepted only in response to a Request for Applications (RFA) announced in the NIH Guide for Grants and Contracts.

The Pancreas Program encourages research into the structure, function, and diseases (excluding cancer and cystic fibrosis) of the exocrine pancreas. Research efforts focus on:

• Neurohormonal factors involved in the regulation of pancreatic exocrine function in response to pathophysiological stimuli
• Studies on receptor and function of intra-cellular signal transducing molecules, coupling to downstream effectors
• Compartmentalization of enzymes, substrates, and their effectors
• Understanding post-translational mechanisms that account for the fate of proteins, including folding, trafficking, and secretion
• Understanding the properties and functions of intracellular and extracellular filamentous suprastructures that are involved in hormone signaling and exocrine pancreatic functionStudies on the biochemistry, etiology, pathogenesis, genetics, epidemiology, diagnosis, treatment, and prevention of disorders of the exocrine pancreas
• Development of experimental models
• Studies relating to development of the exocrine pancreas, including the growth and differentiation factors involved in this process and the characterization, isolation, production, and uses of pancreatic stem cells
• Studies on organ collection, preservation, and transplantation.

The Genetics and Genomics of Digestive Diseases Program supports research on identification of genes influencing predisposition to diseases of the gut, liver, and exocrine pancreas, as well as studies of control of gene expression during normal development and disease states of these organs.

Epidemiology Research

The Epidemiology and Data Systems Program serves as a focus for the collection, analysis, and dissemination of data on digestive diseases and their complications. The program:

• Identifies the data needed to address the scientific and public health issues in digestive diseases and nutrition
• Addresses the epidemiology of digestive diseases and nutritional disorders of public health significance, with particular emphasis on national surveys and their follow-up
• Promotes the timely availability of reliable data to pertinent scientific, medical, and public organizations
• Promotes the standardization of data collection and terminology in clinical and epidemiological research
• Works closely with members of the scientific community to develop investigator-initiated research in digestive diseases and nutrition epidemiology.

The program encourages research that addresses risk factors for disease occurrence and disease prognosis or natural history. The program also supports databases and biological repositories that support clinical and epidemiological studies in digestive diseases and nutrition.

Liver Disease Research Programs

The Liver and Biliary Program supports basic and clinical research on both the normal function and the diseases of the liver and biliary tract. Areas of basic research include:

• Hepatic regeneration; gene therapy; and liver cell injury, fibrosis, and apoptosis
• Basic and applied studies on liver transplantation, including techniques of preservation and storage
• Metabolism of bile acids and bilirubin
• Physiology of bile formation
• Control of cholesterol levels in bile
• Gallbladder and bile duct function.

Areas of disease-oriented research include:

• Cholesterol and pigment gallstones
• Inborn errors in bile acid metabolism
• Chronic hepatitis that evolves from autoimmune, viral, or alcoholic liver disease
• Various liver ailments such as Wilson's disease, primary biliary cirrhosis, primary sclerosing cholangitis, portal hypertension, hepatic encephalopathy, and Crigler-Najjar syndrome.

The Clinical Trials in Liver Disease Program supports patient-oriented clinical research in liver diseases to evaluate one or more experimental intervention(s) in comparison with a standard treatment and/or placebo control among comparable groups of patients. Experimental interventions may include pharmacologic, nonpharmacologic, and behavioral interventions given for disease prevention, prophylaxis, diagnosis, or therapy. Areas of program emphasis in liver disease include non-alcoholic steatohepatitis (NASH); chronic hepatitis C; primary biliary cirrhosis; primary sclerosing cholangitis; prevention, management, and treatment of portal hypertension; and recurrent liver disease after transplantation. Either pilot studies or phase III trials may be appropriate. A phase III clinical trial usually involves several hundred or more comparable human subjects, the aim of the trial being to provide evidence for support of, or a change in, health policy or standard of care.

The NIDDK's HALT-C ( Hepatitis C Antiviral Long-Term Treatment against Cirrhosis) trial is a multi-center, randomized controlled study designed to determine if long-term treatment with peginterferon in previous non-responders with advanced hepatic fibrosis can prevent cirrhosis and reduce the risk of developing end-stage liver disease and hepatocellular carcinoma. Antiviral therapy with peginterferon and ribavirin leads to a sustained virological response in approximately half of patients with chronic hepatitis C. Patients who achieve a sustained loss of hepatitis C virus (HCV) usually have marked improvements in liver histology. Lesser but important degrees of improvement in liver histology also occur in interferon-treated patients who fail to achieve a virological response. Furthermore, data from a recent controlled study suggest that continuing interferon in non-responder patients can maintain the histological improvements. Interferon therapy may also reduce the incidence of hepatocellular carcinoma and improve survival in patients with cirrhosis.

In this trial, non-responders to previous treatment with interferon, interferon and ribavirin, or peginterferon were retreated initially with peginterferon alfa-2a (Pegasys, Roche Pharmaceuticals) in a dose of 180 mcg/week and ribavirin in a dose of 1,000 to 1,200 mg/day for 24 weeks (the lead-in phase). Those who became HCV RNA negative were continued on treatment for 48 weeks, whereas those who remained HCV RNA positive entered the formal protocol and were randomly assigned either to continue treatment with peginterferon alfa-2a alone (90 mcg/week