Program Descriptions A-E

Acute Liver Failure Study Group

Acute liver failure is an uncommon but serious and distinctive clinical syndrome marked by sudden onset of signs of hepatic failure in patients without pre-existing liver disease. Acute liver failure is estimated to cause 2000 deaths yearly and to account for at least 5% of liver transplants in the United States. Traditionally, the most common causes of acute liver failure were believed to be hepatitis A and B, mushroom poisoning and medication-induced liver injury. Recent information, however, indicates that hepatitis A and B are now relatively uncommon causes of acute liver failure and that the majority of cases are either drug-induced or idiopathic. Liver transplantation can be successful in patients with acute liver failure, but criteria for transplantation and predictors of good outcome are not well defined. Importantly, there are no effective medical therapies short of liver transplantation for this severe and frequently fatal syndrome. Clearly, there are many unresolved issues in acute liver failure, and better information is needed on its causes, clinical management and outcome.

To address these issues, Dr. William Lee and coworkers at the University of Texas Southwestern created the Acute Liver Failure Study Group (ALFSG). Funded in 1997 as a small grant (R03) from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the ALFSG initially consisted of a consortium of 14 U.S. academic centers, each of which collected structured information on all cases of acute liver failure seen at their institutions. The group initially assembled retrospective data on cases seen between 1994 and 1996 and provided valuable information on the etiology and outcome of acute liver failure in the United States (Liver Transpl Surg 1999;5:29-34). The ALFSG began collecting prospective data and serum samples in 1998 and the study was eventually expanded to include 24 adult centers. Continued funding for the ALFSG was obtained from the Food and Drug Administration's Office of Orphan Drug Products Development to develop a clinical trial on the use of N-acetylcysteine (NAC) for acute liver failure not caused by acetaminophen overdose. Full funding for the ALFSG came in 2000 with the awarding of a large five-year R01 from NIDDK to support the acute liver failure database and a prospective, randomized, double-blind placebo controlled trial of NAC in acute liver failure. The protocol and informed consents for this trial were approved in 2001, and patient accrual began. As of May 2004, 691 adult patients have been entered into the prospective database, and approximately half of a planned total of 200 patients have been enrolled in the controlled trial of NAC. The study is monitored by an independent data and safety monitoring board which has access to the unblinded data at specified intervals. To date, no serious adverse events attributable to NAC have occurred.

Concurrently, a pediatric component of the ALFSG has been developed. Under the direction of Dr. Robert Squires at the University of Pittsburgh, a total of 24 pediatric centers have joined in the study group, and 294 pediatric patients have been entered into the database. The trial of NAC for acute liver failure in children has recently been approved and the first patients have been enrolled.. An important rationale for the ALFSG was to provide prospective surveillance of acute liver failure in the United States, focusing on the relative frequency of different etiologies and changes over time. The study group also provides a means of assembling adequate numbers of well-defined cases of acute liver failure to allow for clinical description, such as for bromfenac (Liver Transpl Surg 1999;5:480-484) and troglitazone (Dig Dis Sci 2000; 45:549-553). The database also allows for characterization of specific risk factors for medication-induced liver damage such as alcohol intake in cases of acetaminophen toxicity. Importantly, the ALFSG has accrued well-characterized cases of acute liver failure with accompanying serum, tissue and DNA samples that will allow for viral and genetic characterization (Hepatology 2001;33:972-976). This study will be invaluable as a resource for viral discovery and genetic and immunological approaches to defining the cause(s) of idiopathic acute liver failure.

The ALFSG is an example of an investigator-initiated research project that has matured into a potent means of supporting multicenter, clinical and basic research on an important liver disease. This study group serves as a model for the development of clinical consortia focused on specific issues in liver disease and aimed at stimulating "bedside-to-bench" research. More information on this consortium is available at www3.utsouthwestern.edu/liver

Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL)

Liver transplantation is now the standard of care for patients with end-stage liver disease. At present, more than 4,500 liver transplants are done yearly. Unfortunately, more than 18,000 patients are awaiting liver transplantation, and in recent years, the waiting list has continued to grow. As a consequence, the numbers of patients dying on the liver transplant waiting list has grown. The introduction of the MELD system was designed to assign livers to the patients in most critical need for transplantation and, thereby, decrease the waiting list mortality. While this approach may have been partially successful, the continued shortage of cadaveric livers and continued growth of demand for liver transplantation will mean that the mortality rate on the waiting list will continue to be high.

Among possible remedies to the shortage of cadaveric livers for transplantation, living donor liver transplantation is perhaps the most practicable, but also the most controversial. Living donor liver transplantation has become widely accepted for pediatric patients. For children, the left lobe of an adult liver is adequate for transplantation, and left-lobe living donor liver transplantations (particularly from parent to child) have been done successfully for more than a decade. For adults, transplantation of a left lobe of the liver (approximately 20-30% of the liver mass) is usually inadequate to support life, particularly in a patient already suffering from end-stage liver disease. Transplantation of the right lobe (50-60% of the liver mass) can be successful in adults, but the donor operation is accordingly more extensive and more life-threatening. Adult-to-adult living donor liver transplantation was first accomplished in the late 1990s and was introduced into the United States in 1997. Since then, the numbers of adult-to-adult living donor transplants has grown considerably, now accounting for approximately 5% of all liver transplants done in the United States. Nevertheless, the donor operation in adult-to-adult liver transplantation is challenging and potentially dangerous. Indeed, between 1998 to 2003, there were at least two deaths of healthy, adult donors after adult-to-adult living donor liver transplantation.

To address the issues of the proper use, relative risks and potential benefits of adult-to-adult living donor liver transplantation, the NIDDK established a multicenter clinical cohort study. The "Adult-to-Adult Living Donor Liver Transplantation Cohort Study" (A2ALL) consists of nine liver transplant centers experienced in performing living donor liver transplantation and a data coordinating center responsible for directing and maintaining an infrastructure of a clinical database on patients. The primary goal of A2ALL will be to provide valuable information on the outcomes of living donor liver transplantation. The cohort study will follow both donors and recipients before and after the liver transplant operation assessing clinical outcomes and quality of life. This information is needed to aid decisions made by physicians, patients, and potential donors.

Principal Investigators and A2ALL Liver Transplant Centers.

• Mike Abecassis, M.D., Northwestern Memorial Hospital


• Carl Berg, M.D., University of Virginia Health System


• Mark Ghobrial, M.D., Ph.D., University of California Los Angeles Healthcare


• Jean Emond, M.D., Columbia University Health Sciences


• Robert A. Fisher, M.D., Virginia Commonwealth University Health System


• Chris E. Freise, M.D., University of California, San Francisco Health Center


• Abraham Shaked, M.D., University of Pennsylvania Health System


• Roshan Shrestha, M.D., University of North Carolina Health Care


• James F. Trotter, M.D., University of Colorado Health Sciences Center

Principal Investigator, A2ALL Data Coordinating Center

• Robert Merion, M.D., University of Michigan Heath System Project Officer for A2ALL, NIDDK


• Jay Everhart, M.D., M.P.H., Division of Digestive Diseases and Nutrition, NIDDK

National Institutes of Health, Project Officer for A2ALL, NIDDK

• James Everhart, M.D., M.P.H.,
• Dr. Patrica Robuck, Co-Project Officer
• Dr. Leonard Seeff, Scientific Advisor

The A2ALL cohort study was initiated in September 2002 and patient data accrual is due to begin in August 2003. More information is on the website: www.nih-2all.org/default.asp

Acquired Immunodeficiency Syndrome (AIDS) and Human Immunodeficiency Virus (HIV)

Each of the three divisions in NIDDK support an AIDS and HIV program. The Division of Digestive Diseases and Nutrition encourages research into the characterization of intestinal injury, mechanisms of maldigestion, and intestinal mucosal functions, as well as hepatic and biliary dysfunction in patients with AIDS or in appropriate animal models. In addition, studies are supported on the mechanisms of nutrient malabsorption, deficiencies of various micronutrients, nutritional management of the wasting syndrome, and other aspects of malnutrition related to AIDS.

The HIV program in the Division of Kidney, Urologic, and Hematologic Diseases supports basic and clinical studies on renal and genitourinary tract structure and function and hematopoietic function in individuals with HIV infection. Interests include (1) the pathogenetic mechanisms of the viral infection on the kidney and genitourinary tract, (2) sites of viral replication and/or spread and the resulting organ dysfunction, and (3) hematologic abnormalities associated with HIV infection and its effects on stem cells and marrow function. Studies on HIV infection focus on the (1) effect of HIV therapies on marrow function and clinical course of dialysis and transplant patients, (2) potential interactions of HIV infection and therapies on the immunosuppressive therapy used to prevent transplant rejection, and (3) effect on organ function. An important new emphasis is research into the development of strategies for gene therapy for HIV, using modification of hematopoietic stem cells. This research is based on recent reports of protection against HIV through the use of human fetal stem cells transduced with retroviral vectors expressing a ribozymal gene.

The Division of Diabetes, Endocrinology, and Metabolic Diseases is interested in the metabolic complications of HIV infection, which encompass research on the endocrine and body composition abnormalities associated with HIV infection and its treatment.

Specific areas of support include:

• Studies of hormones and cytokines involved in wasting syndromes.
• Studies of changes in body composition in HIV patients.
• Studies of abnormalities of insulin sensitivity (and other components of the "Metabolic Syndrome" or "Syndrome X") in patients with HIV.

For further information, contact:

Frank Hamilton, M.D., M.P.H., DDDN, Gastrointestinal Mucosa and Immunology Program Director.
David G. Badman, Ph.D., DKUH, Hematology Program Director
Catherine Meyers, M.D., DKUH, Inflammatory Kidney Diseases Program Director
Teresa Jones, M.D., DDEM, Diabetes Complications Program Director

Adipocyte Biology

The Adipocyte Biology Research Program supports research that addresses the development and physiology of the adipocyte cell. Animal and tissue culture models would be included in the approaches used in this area. Studies on the properties of transcription factors that regulate adipocyte differentiation would be appropriate to this program. Research on the consequences of insulin action on adipocyte physiology would be particularly suitable to this research program.

For further information, contact Carol Haft, Ph.D., Director, Adipocyte and Cell Biology Program

Autoimmunity/Viral Etiology of Type 1 Diabetes

This 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 which emphasize autoimmune thyroid disease, including Graves' Disease, Hashimoto's thyroiditis, and their complications are included. Humanized animal models of AITD are also included.

For further information, contact Lisa Spain, Ph.D., Director, Immunobiology of Type 1 Diabetes Program

Basic Cell Biology of the Bladder and Prostate

The DKUH Basic Cell Biology Program acts to foster scientific investigations aimed at understanding the fundamental cellular and molecular mechanisms operating under normal and diseased states. This program oversees a diverse array of scientific endeavors relevant to the mission of the NIDDK with primary emphasis on basic research in the bladder, prostate, urinary tract, kidney, and the lower reproductive system. Supported work includes studies in human cells as well as in mammalian and non-mammalian model organisms.

The Basic Cell Biology Program supports cellular and molecular research on numerous topics including, but not limited to, the following:

• Cellular function during renal and urologic disease
• Urothelial biology
• Host-pathogen interactions in urinary tract infections
• Urologic markers of disease
• Urologic complications of diabetes
• Urinary smooth muscle function
• Neural signaling in the urologic system
• Prostate growth and development
• Prostate stem cells
• Cellular events influencing sexual health
• Polarized cellular trafficking
• Kidney receptor function/signaling
• Organelle biogenesis

For further information, contact Christopher Mullins, Ph.D.,
DKUH, Director, Basic Cell Biology of the Bladder and Prostate Program.

Basic Renal Biology

Research supported by the Renal Physiology/Cell Biology Program focuses primarily on the normal development, structure, and function of the kidney, including its biochemistry, metabolism, transport, and fluid electrolyte dynamics.

Research is supported on the cellular and subcellular molecular mechanisms involved in transport processes that regulate solute and water excretion, with emphasis on how abnormalities in these transport processes and enzymes may contribute to disease states such as renal stones, hypertension, acid-base abnormalities, and progression of renal disease. Of special interest are studies to elucidate factors that contribute to acute renal failure, which will lead to its prevention or make the disease less severe and, ultimately, speed recovery of kidney function.

This program emphasizes applying cellular and molecular biologic techniques to identifying and characterizing growth factors and signal transduction systems and transport systems and respective genes, and to elucidating the structure of genes and their regulation during kidney organogenesis, which may continue to operate in the mature kidney.

For further information, contact Chris Ketchum, Ph.D., Basic Renal Biology Program Director.

Behavioral/Prevention Research in Diabetes

The division supports a substantial portfolio of culturally sensitive, lifestyle interventions to prevent or treat diabetes in diverse high-risk populations including African-Americans, Hispanic Americans, and Native Americans. This research includes individual, family, and community-based strategies aimed at prevention of diabetes and its complications through lifestyle modifications. The link between behavior and physical health is an important focus of research. Approaches to improving health-related behaviors and to enhancing diabetes self-management and other aspects of diabetes care are supported both through RO1s and centers.

For further information, contact Sanford Garfield, Ph.D., Senior Advisor for Biometry and Behavioral Research.

Beta Cell Therapy

Type 1 and type 2 diabetes result from the anatomical and functional loss of insulin-producing beta cells of the pancreas. Replacement of these cells through regeneration or transplantation could offer lifelong treatment for diabetics. However, a major problem in implementing treatment is the lack of sufficient islet cell tissue for transplantation, and a lack of understanding of how beta cells regenerate. To overcome the shortage of pancreatic islets for transplantation, 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 is needed.

This program will support 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

For further information, contact Sheryl Sato, Ph.D., Beta Cell Biology and Neuroendocrinology Program Director.

Biliary Atresia Research Consortium

Neonatal liver disease affects 1 in 2,500 liver births and its major cause is biliary atresia. At present, biliary atresia is the single most common reason for liver transplantation in children and is a major challenge for early detection, diagnosis, and management. At the same time, the underlying cause of biliary atresia is unclear. The disease is congenital but does not appear to be familial or inherited. Various hypotheses have been advanced to explain the occurrence of biliary atresia, but none have proven to be true or to lead to a practical means of early detection, diagnosis, treatment or prevention. Because biliary atresia and other forms of neonatal liver disease are rare, no single referral center in North America cares for enough new patients each year to allow for intensive analysis of etiology and risk factors or to critically assess novel means of diagnosis or treatment. For these reasons, the NIDDK established a "Biliary Atresia Clinical Research Network" (BARC). The consortium is charged with establishing and maintaining the infrastructure for accruing sufficient numbers of biliary atresia and neonatal hepatitis patients to perform adequately powered clinical studies. The overall goal of this consortium is to gather clinical and biochemical data and adequate numbers of serum, tissue, and DNA samples in a prospective manner to facilitate research and generate new hypotheses and test existing hypotheses on the pathogenesis and optimal diagnostic and treatment modalities of these disorders. It is also hoped that the establishment of this consortium and the serum and tissue bank will stimulate other scientists to develop an interest in investigating the etiology and pathogenesis of these disorders and collaborate with the consortium, with serum and tissue being made available for appropriate studies. The study is funded by the NIDDK and the Office of Rare Disorders. At present BARC consists of nine pediatric liver disease Clinical Centers and a Data Coordinating Center.

To date, BARC has established both a prospective and a retrospective database for children with biliary atresia seen at the 9 Clinical Centers. The BARC investigators have also designed a prospective controlled trial on the use of high-doses of corticosteroids at the time of the portoenterostomy (the Kasai Procedure) for biliary atresia. The use of corticosteroids during the peri-operative period has been reported to improve bile flow and the outcome of portoenterostomy, but this benefit has never been proven in a prospective, controlled manner, and high dose corticosteroids have the potential of causing harm. Thus, this randomized controlled trial will address an important issue in management of biliary atresia and set the standard for future studies.

Importantly, BARC has recently been expanded to include studies of children with other serious cholestatic liver diseases. This expansion was made possible by the awarding of a Rare Disease Clinical Research Network to the BARC investigators with joint funding from the Office of Rare Diseases and the NIDDK. This component is the "Cholestatic Liver Disease Consortium" which will focus on five liver conditions that affect children: Alagille syndrome, progressive familial intrahepatic cholestasis (PFIC), alpha-1-antitrypsin deficiency-associated liver disease, the mitochondrial hepatopathies, and inborn errors of bile acid metabolism. Special core centers will be funded for studies of genetics, bile acid metabolism and liver pathology. Children with these conditions will be enrolled in a prospective database. CLIC will also include patient education and outreach activities and provide a national resource for information and future research opportunities on these rare liver diseases.

Principal Investigators and Clinical Centers (BARC)
Barbara Haber, M.D., Children's Hospital of Philadelphia,
David Perlmutter, M.D., Ph.D., Children's Hospital of Pittsburgh,
Peter Whitington, M.D., Children's Memorial Hospital in Chicago,
Jorge Bezerra, M.D., Cincinnati Children's Hospital and Medical Center,
Kathleen Schwarz, M.D., Johns Hopkins Hospital,
Benjamin Shneider, M.D., Mount Sinai Hospital of NYC,
Ross Shepherd, M.D., St. Louis Children's Hospital/Washington University,
Phillip Rosenthal, M.D., University of California at San Francisco,
Ronald Sokol, M.D., University of Colorado/The Children's Hospital of Denver.

Data Coordinating Center and Principal Investigator (BARC):
Morton Brown, Ph.D., the University of Michigan in Ann Arbor.

Staff from Division of Digestive Diseases and Nutrition, NIDDK:
Patricia R. Robuck, Ph.D., M.P.H. Project Officer
Ed Doo, M.D., Scientific Advisor
Jay Hoofnagle, M.D., Scientific Advisor

Bone and Mineral Metabolism

The Bone and Mineral Metabolism Program encompasses basic and clinical research on the hormonal regulation of bone and mineral metabolism in health and disease. Specific areas of support include (1) endocrine aspects of disorders affecting bone, including osteoporosis, Paget's disease, renal osteodystrophy, and hypercalcemia of malignancy; (2) pathogenesis, diagnosis, and therapy of parathyroid disorders, including primary or secondary hyperparathyroidism; (3) effects of parathyroid hormone (PTH), parathyroid hormone related protein (PTHrP), calcitonin, vitamin D, estrogen, retinoic acid, growth factors (e.g. IGF-I, etc.), glucocorticoids, thyroid hormone, and other systemic or local-acting hormones and their receptors on bone metabolism; (4) bone active cytokines (e.g. TGF-b, BMPs, CSF-1); (5) studies of calcium homeostasis, absorption, metabolism, and excretion, including the calcium activated receptor (CaR); (6) basic and clinical studies of vitamin D; and (7) bone morphogenesis, including the roles of developmental factors in bone formation (e.g. hedgehogs, Hox genes).

For further information, contact Ronald Margolis, Ph.D., Senior Advisor, Molecular Endocrinology and Associate Director for Grants Administration.

Centers for Research in Kidney, Urologic, and Hematologic Diseases

Chronic Renal Diseases

The Chronic Renal Diseases Program supports basic and clinical research on renal development and disease, including (1) causes, pathogenetic mechanisms, and pathophysiology; (2) morphological and functional markers and diagnostic measures; (3) underlying mechanisms leading to progression of renal disease; (4) functional adaptation to progressive nephron loss; (5) natural history of progressive renal diseases; and (6) identification and testing of possible therapeutic interventions to prevent development or halt progression of renal disease.

Research in this program includes the primary glomerulopathies and renal disease from systemic diseases that collectively account for more than 50 percent of all cases of treated end-stage renal disease.

Of special interest are studies of inherited diseases such as polycystic kidney disease, congenital kidney disorders, and immune-related glomerular diseases including IgA nephropathy and the hemolytic uremic syndrome.

For further information, contact Lawrence Agodoa, M.D., Chronic Renal Disease Program Director.

Clinical Nutrition Research Units (CNRU)

A Clinical Nutrition Research Unit (CNRU) is an integrated array of research, educational, and service activities focused on human nutrition in health and disease. It serves as the focal point for an interdisciplinary approach to clinical nutrition research and for the stimulation of research in areas such as improved nutritional support of acutely and chronically ill persons, assessment of nutritional status, effects of disease states on nutrient needs, and effects of changes in nutritional status on disease. Funding for the CNRU program, which began in 1979, is provided through the core center grant mechanism. Due to a restriction in 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.

Please see the DDN Centers page.

For further information, contact Carolyn Miles, Ph.D. Clinical Nutrition Research Unit Program/Obesity/Nutrition Research Centers Program Director, DDN Clinical Obesity and Nutrition Program Director, Obesity Nutrition Research Center and Clinical Nutrition Research Unit Program Director, Program Director Carolyn Miles, Ph.D., 2 Democracy Plaza, Rm. 665 (301) 451-3759

Clinical Obesity and Nutrition Program

The Clinical Obesity and Nutrition Program emphasizes support of investigator-initiated clinical research relating to biomedical and behavioral aspects of obesity and nutrition. This program encompasses clinical studies of obesity investigating appetite and food intake, energy expenditure (including physical activity), body composition, or impact of obesity or its treatment (including medical/surgical therapies) on metabolic factors, psychosocial factors, or co-morbid conditions. The physiological and metabolic consequences of weight loss or weight gain, the effects of exercise and diet composition on appetite and weight control, and the individual variability in energy utilization and thermogenesis in humans are contained within the specific research interests of this program. Investigations incorporating improved methods for assessment of body composition, examination of health risk factors with specific degrees of obesity or body composition, and determination of the effect of exercise on body composition also are supported. Pilot and Single-site investigator initiated clinical trials in nutrition in which the purpose of the study is to assess the impact of a nutritional intervention on a non-weight related health outcome are also encompassed within this program. Clinical trials in which the goal of the study is to assess methods to prevent weight gain or induce weight loss are contained within the Obesity Prevention and Treatment Program. Multisite Nutrition clinical trials are encompassed in the Nutrition Clinical Trials Program. Clinical studies related to the requirement, bioavailability, and metabolism of nutrients and other dietary components at the organ, cellular, and subcellular levels in normal and diseased states are contained within the Nutrient Metabolism Program. Observational studies or studies using secondary data analysis are appropriate for theNutritional Epidemiology Program. Studies with a major focus on the genetics or genomics of obesity are encompassed within the Obesity Genetics and Genomics Program. For further information, contact Carolyn Miles, Ph.D., Clinical Obesity and Nutrition Program Director

Clinical Trials in Liver Diseases

This 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.

Clinical trials and prospective clinical studies in liver disease that are currently funded by the Division of Digestive Diseases and Nutrition include:

• HALT-C, a study of long-term therapy with peginterferon in patients with chronic hepatitis C and advanced fibrosis who have failed to respond to standard therapy;
• Virahep-C, a study of peginterferon and ribavirin combination therapy in African American and Caucasian patients focusing upon the frequency and biological basis for non-response to antiviral treatment;
• Peds-C, a study of peginterferon with or without ribavirin as therapy of hepatitis C in children and adolescents;
• Nonalcoholic " Steatohepatitis (NASH) Clinical Research Network, a prospective database and " natural history study that includes a prospective randomized controlled trial in adults of a thiazolidinedione (pioglitazone) versus vitamin E or placebo and a similar trial in children of metformin versus vitamin E or placebo as therapy for NASH;
• Biliary Atresia Clinical Research Consortium (BARC), which is a prospective database on children with biliary atresia and includes a prospective randomized controlled trial of corticosteroids vs. placebo for improvement of bile flow after portoenterostomy surgery. BARC has recently been expanded to include a prospective study of children with rare neonatal cholestatic liver diseases (Cholestatic .Liver Disease Consortium: CLIC) including Alagille syndrome, alpha-1-antitrypsin deficiency, progressive familial intrahepatic cholestasis (PFIC), mitochondrial hepatopathy and inborn errors of bile acid metabolism;
• Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL), which is a prospective and retrospective database on both donors and recipients of a living donor liver transplant which focuses on issues of donor informed consent and the quality of life, disease recurrence, and survival of recipients after liver donor liver transplantation; A2ALL is also initiating a randomized controlled trial of peginterferon and ribavirin therapy for patients with chronic hepatitis C (genotype 1) awaiting living donor liver transplantation;
• Acute Liver Failure Study Group, a prospective database and natural history study of acute liver failure and a randomized controlled trial of" N-acetyl cysteamine for patients with acute liver failure that is not due to acetaminophen;
• Drug-Induced Liver Injury Network (DILIN), which is a prospective and retrospective database on cases of drug-induced liver injury.
• High dose Ursodiol Therapy for Primary Sclerosing Cholangitis, which is a prospective randomized controlled trial of ursodiol versus placebo being conducted by five clinical centers.

Clinical trials may be funded by one of several mechanisms: a research project grant, a cooperative agreement, a planning grant, or a contract. Please see the current program announcement for small grants for clinical trials. For more information, contact Patricia R. Robuck, Ph.D., M.P.H., Program Director for Clinical Trials in Liver Diseases.

For more information, contact Patricia R. Robuck, Ph.D., M.P.H., Program Director for Clinical Trials in Liver Diseases.

Clinical Trials in Digestive Diseases

This 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 two or more treatments, one 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.

Clinical trials may be funded by one of several mechanisms: a research project grant, a cooperative agreement, a planning grant, or a contract.  Please see the current program announcement for small grants for clinical trials.

For more information, contact Patricia R. Robuck, Ph.D., M.P.H., Clinical Trials Program Director.

Clinical Trials in Nutrition

This program supports clinical research on nutrition and eating disorders, focusing on metabolic and/or physiologic mechanisms. 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 http://grants1.nih.gov/grants/guide/pa-files/PAR-01-056.html for small grants for clinical trials. Phase III clinical trials usually are multi-center and involve several hundred human subjects that are randomized to two or more treatments, one of which is a placebo. The aim of the trial is to provide evidence for support of, or a change in, health policy or standard of care.

For more information, contact Patricia R. Robuck, Ph.D., M.P.H., Clinical Trials Program Director.

Clinical Research in Type 2 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 and improving the care of patients with type 2 diabetes.

For further information on Type 2 Diabetes in the Pediatric Population, contact Barbara Linder, M.D., Ph.D., Senior Advisor for Childhood Diabetes Research

For information on Type 2 Diabetes in the Adult Population contact Myrlene Staten, M.D., Senior Advisor for Diabetes Research Translation.

Complications of Diabetes

The Complications of Diabetes 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

For further information, contact Teresa Jones, M.D., Director, Diabetes Complications Program

For further information on Diabetes Complications (SBIR, STTR only), contact Kristin Abraham, Ph.D., Director, Cell Signaling Program

Conference Grants & Cooperative Agreements

Conference Grant, Traditional (R13)

Conference Grants are awarded to institutions and organizations (not individuals) to provide partial support for international or domestic meetings, conferences, and workshops to coordinate, exchange, and disseminate research information. NIDDK is especially interested in conference grants used to cover travel expenses for young and minority investigators, although meeting publications, salaries, consultant services, equipment rental, and supplies may be requested. Indirect costs normally are not allowed.

For more information, contact Dr. M. Ken May, Nutrient Metabolism Program Director

Conference Cooperative Agreement (U13)

The Conference Cooperative Agreement is a relatively new mechanism that allows NIDDK staff to play a substantial role in planning and conducting meetings, conferences, and workshops sponsored by other institutions or organizations. Refer to "Conference Grant" above for more information on costs that may be covered by this award.

For more information, contact Dr. M. Ken May, Nutrient Metabolism Program Director

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 transport of molecules other than chloride, post-translational 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 which explain the variable clinical presentations and severity of disease
• Delineation of the mechanisms underlying the inflammation and infection characteristic of cystic fibrosis and 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, and 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 study of cystic fibrosis and its therapy
• Evaluation of therapeutic interventions in cystic fibrosis in clinical studies or animal models.

For further information, contact Catherine McKeon, Ph.D., Senior Advisor for Genetic Research.

Developmental Biology

Developmental genetic screens for identifying mutations that effect the formation of tissue such as bone, adipose, endocrine pancreas, or pituitary.

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.

For further information, contact Sheryl Sato, Ph.D., Beta Cell Biology and Neuroendocrinology Program Director.

Developmental Biology of the Kidney and Urogenital Tract

The Developmental Biology of the Kidney and Urogenital Tract Program encompasses studies that focus on fundamental cellular biology of the kidney and urogenital tract (bladder and prostate) and on mechanisms through which they develop. Specific areas of study are as follows:

Developmental Biology (Kidney)

• Stem cells and cell fate specification
• Mesenchymal/epithelial/stromal interactions during development
• Tubule morphogenesis
• Differentiation of the renal epithelium
• Renal endothelial/glomerular morphogenesis

Cell Biology (Kidney)

• Mechanisms of epithelial polarization
• Epithelial integrity and repair
• Cilia: components and functions
• Epithelial/stromal/endothelial interactions

Development of the Urogenital Tract. (Bladder and Prostate)

• Stem cells and cell fate specification
• Differentiation of the bladder and prostate epithelia
• Innervation of the urogenital system during development
• Mesenchymal/epithelial interactions
• Smooth muscle specification and differentiation
• Vascularization
• Roles of intercellular signals and extracellular matrix in development

For further information, contact Elizabeth Wilder, Ph.D., Developmental Biology of the Kidney and Urogenital Tract Program Director.

Diabetes Centers

The Diabetes Centers Program administers two 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 two types of centers differ in that the DERC focuses entirely on biomedical research while the DRTC has an added component in training and translation.

For further information, contact Kristin Abraham, Ph.D., Director, Cell Signaling Program

Diabetic Nephropathy

The Diabetic Nephropathy Program funds basic research on the pathophysiology and pathogenesis of diabetic nephropathy, natural history studies, and clinical trials through the R01 mechanism. Fundamental research focuses on the molecular pathogenesis of extracellular matrix expansion and glomerulosclerosis, the role of the renin-angiotension system and growth factors, and the identification of treatments to prevent renal scarring.

Of special interest are studies to understand the mechanisms of progressive renal scarring, to identify genes that either protect people from or predispose them to diabetic nephropathy, and to identify early markers of increased risk for the disease.

For futher information, contact Catherine Meyers, M.D., DKUH, Inflammatory Kidney Diseases Program Director

Digestive Diseases and Nutrition Epidemiology and Data Systems

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 (1) identifies the data needed to address the scientific and public health issues in digestive diseases and nutrition; (2) addresses the epidemiology of digestive diseases and nutritional disorders of public health significance, with particular emphasis on national surveys and their follow-up; (3) promotes the timely availability of reliable data to pertinent scientific, medical, and public organizations; (4) promotes the standardization of data collection and terminology in clinical and epidemiological research; and (5) 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.

For further information, contact James Everhart, M.D., Chief of Epidemiology and Clinical Trials Branch, DDN.

Digestive Diseases Research Core Centers (DDRCCs)

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.

Please see the Centers page.
Schedule of Review for DDRCCs

For further information, contact Judith Podskalny, Ph.D., Digestive Diseases Centers Program Director.

Drug-Induced Liver Injury Network (DILIN)

Liver injury due to medications is one of the most common causes of acute liver disease and jaundice. Importantly, the mortality rate of hepatic idiosyncratic drug reactions is quite high, and over half of cases of acute liver failure in the United States are due to adverse reactions to medications. Elucidation of the mechanisms of hepatic drug injury, however, is often difficult. Drug-induced liver disease is typically unpredictable, idiosyncratic and rare. Most of the medications that cause acute liver injury in humans, do not produce injury in experimental animals. Attribution of acute liver injury to a medication is frequently difficult: the patient with hepatotoxicity often has multiple other risk factors for liver disease, may be on many potentially hepatotoxic drugs, and may not present until the injury has resolved. Drug-induced liver injury is also quite variable in clinical expression. Patterns of injury mimic virtually all other forms of liver disease, including acute viral hepatitis, autoimmune liver disease, bland cholestasis, mixed cholestatic-hepatic syndromes, acute cholangitis, microvesicular steatosis with lactic acidosis, alcohol-like steatohepatitis, and veno-occlusive disease. Finally, drugs that cause hepatotoxicity are usually withdrawn from use, and the mechanism of injury remains unknown and no longer available for study. Despite the clinical significance of drug-induced liver injury, this form of liver disease is a relatively unstudied area of research. Part of the difficulty in studying drug-induced liver disease is the absence of a sufficient cohort of well-characterized patients in whom to carry out clinical, genetic, immunological and biochemical investigation. To help develop a prospective database on drug-related hepatotoxicity, the NIDDK has established a "Drug-Induced Liver Injury Network" - DILIN. The Network consists of five interactive clinical centers and a data coordinating center. The objective of the Network is to develop standardized definitions and instruments to identify and characterize bone fide cases of drug-induced liver injury to allow for analysis of the epidemiology and clinical spectrum of hepatotoxicity and to identify cases of medication-induced liver disease prospectively which will allow for collection of biological samples that can be used for the study of the pathogenesis of hepatotoxicity using biochemical, serological and genetic techniques. The Network will be expected to collaborate with other investigators in the areas of hepatocyte biology and cell injury as well as pharmacokinetics and pharmacogenetics. A repository will be established for storage of serum, tissue and DNA samples. The Network will be funded as a pilot phase (3 years) which, if successful, will be extended by future RFAs.

To date, DILIN has developed protocols for both a retrospective and prospective studies of drug-induced liver disease. The retrospective study will focus on four drugs that are well-known causes of hepatotoxicity: isoniazid, phenytoin, valproate, and clavulanate/ amoxicillin. A minimum of 50 cases of each form of drug-induced liver disease will be sought along with suitable number of controls. Clinical information will be retrieved for each patient and DNA obtained for genomic studies. The prospective study will attempt to enroll all cases of drug-induced liver injury seen at the five clinical centers and in their referral, catchment area. Patients will be enrolled during the period of acute injury and prospectively followed. Careful clinical information and laboratory data will be retrieved, and blood, urine, lymphocyte and DNA samples will be obtained suitable for biochemical, metabolomic, transcripteomic and genetic studies. Patients receiving the same implicated drugs without liver injury will also be enrolled and provide control samples for laboratory investigation. The focus of this prospective study will be not only prescription drugs, but also over-the-counter and herbal medications. The DILIN investigators have also developed diagnostic criteria and means of grading causality in drug-induced liver disease and will prospectively assess these instruments for sensitivity and specificity. The overall aim of DILIN is to bring greater focus and interest to the study of drug-induced liver disease and to help develop means of its prevention, early detection, and treatment.

Clinical Centers, Drug-Induced Liver Injury Network

• Paul Watkins, M.D., University of North Carolina, Chapel Hill, NC
• Naga Chalasani, M.D., University of Indiana, Indianapolis, IN
• Timothy Davern, M.D., University of California, San Francisco, CA
• Robert Fontana, M.D., University of Michigan, Ann Arbor, MI
• Herbert Bonkovsky, M.D., University of Connecticut, Hartford, CT

Data Coordinating Center, Drug-Induced Liver Injury Network

• James Rochon, Ph.D., Duke University, Raleigh-Durham, NC

NIDDK Staff

• Jose Serrano, M.D., Ph.D., Program Director
  
• Leonard Seeff, M.D., Scientific Advisor

Endocrine Pancreas

This program includes projects to elucidate the basic biology of the endocrinecells of the pancreas, which include alpha, beta, delta, etc., 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.

For further information, contact Maren Laughlin, Ph.D., Director, Metabolism Program.

End-Stage Renal Disease

The End-Stage Renal Disease Program promotes research to reduce morbidity and mortality from bone, blood, nervous system, metabolic, gastrointestinal, cardiovascular, and endocrine abnormalities in end-stage kidney failure and to improve the effectiveness of dialysis and transplantation. Of special interest is research on hemodialysis membrane reuse and alternative dialyzer sterilization methods; more efficient, biocompatible membranes; high-flux hemodialysis; and criteria for adequacy of dialysis. Also of interest is research on adequacy, appropriate dialysis dose, and infectious complications in peritoneal dialysis, as well as criteria to identify patients best suited for this therapy.

The program seeks to increase graft and patient survival and organ availability through research to improve organ preservation, transplantation across ABO blood groups, HLA cross-matching of donors with recipients, immunosuppression, infection control, and organ donations, especially by African American and other minority groups. Of special interest is research on the causes and prevention of progressive loss of renal function in long-term renal transplants.

For further information, contact Lawrence Y. Agodoa, M.D., End-Stage Renal Disease Program Director.

Epidemiology of Renal and Urologic Disease

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