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Barbara Davis Center for Childhood Diabetes - Research

 

Research into the immunopathogenesis of type 1 diabetes spans both basic and clinical research, with major emphasis on genetic animal models of type 1 diabetes and on type 1 diabetes of humans. The Barbara Davis Center's faculty has pioneered islet biochemistry, immunobiology of islet beta cell transplantation, identification of individuals at risk for developing type 1 diabetes, and trials for the prevention of diabetes and its complications. Locally, the Center initiated DAISY (Diabetes Autoimmunity Study in the Young), which screened and genotyped newborns and their families in the Denver area and continues to follow subjects for antibody positivity and development of type 1 diabetes. With the screening of more than 30,000 newborns for genetic risk of type 1 diabetes at birth, the first study addressing the development of autoimmunity in children from the general population continues to publish new findings in collaboration with the Colorado School of Public Health. The BDC also follows the largest, longest standing national cohort of twins with diabetes in the U.S., with the BDC Twin Family Study.

Research into new therapeutic approaches and prevention of complications to Type 1 diabetes includes pioneering clinical introduction of insulin analogs, continuous glucose monitoring with feedback, control of insulin pumps and epidemiologic studies of micro and macrovascular complications.

The research division is home to the Diabetes and Endocrine Research Center, an NIH-funded program that facilitates diabetes research by providing biomedical core facilities, pilot and feasibility grants, and education and training programs for faculty, research fellows, graduate and undergraduate students. The NIDDK-supported Diabetes Endocrinology Research Centers (DERCs) and Diabetes Research and Training Centers (DRTCs) are part of an integrated program of diabetes and related endocrinology and metabolism research. Centers provide increased, cost-effective collaboration among multidisciplinary groups of investigators at institutions with an established, comprehensive research base in diabetes and related areas of endocrinology and metabolism.

Internationally, the BDC is one of six centers worldwide participating in TEDDY (The Environmental Determinants of Diabetes in the Young), one of whose founders and principal investigators is our Clinical Director, Dr. Marian Rewers. Additionally, clinician researchers at the BDC, including our Executive Director, Dr. George Eisenbarth, were seminal players in the development of TrialNet, a network of 18 clinical centers working in cooperation with screening sites throughout the U.S., Canada, Finland, United Kingdom, Italy, Germany, Australia, and New Zealand. This network is dedicated to the study, prevention, and early treatment of type 1 diabetes and includes the Natural History Study and several intervention studies under the direction of Dr. Peter Gottlieb in the Adult Clinic. A Stem Cell Endowment Fund for the BDC was initiated in 2008, with funding to be partially matched by the Gates Frontiers Fund, a $6 million regenerative medicine and stem cell initiative created by the Charles C. Gates family for programs at the Anschutz Medical Campus.

Other international programs with which BDC researchers are affiliated include T1DGC (Type 1 Diabetes Genetics Consortium), the Brehm Coalition, the ITN (Immune Tolerance Network, which includes several intervention studies), the NIH, the Juvenile Diabetes Foundation Autoimmunity Prevention Centers, and the CACTI Study (Cardiovascular and Arteriosclerosis Complications in the Young).
For a list of affiliated studies and requirements for participation see the Center’s Web site for clinical studies: http://www.ucdenver.edu/academics/colleges/medicalschool/centers/BarbaraDavis/Clinical/Pages/default.aspx.

The Center’s research division has been designated a Juvenile Diabetes Research Foundation (JDRF) BDC Autoimmune Prevention Center (APC), an international collaborative research network of five centers worldwide. The APC supports translational diabetes research and provides additional core facilities for access to human clinical material, immunoassay and lymphocyte phenotyping. Research faculty investigators at the BDC were the first to clone T cells causing type 1 diabetes. T cells play a major role in autoimmunity, both in its development and in its regulation. A key focus in research at the BDC has been the role the immune system plays in the development of diabetes and in the discovery of key islet cell antigens that the immune system attacks to destroy functioning β cells, which produce insulin. Two major antigens were discovered by BDC researchers in the laboratory of its Director of Research, one as recently as the fall of 2007: ZnT8, the zinc transporter.

The BDC also works with pharmaceutical companies to test new insulins, new insulin delivery systems, and state-of-the-art glucose sensing systems, including the new continuous glucose monitoring (CGM) devices. The BDC continues to be actively involved in efforts to increase insurance coverage for insulin pumps, CGMs, and other new technologies associated with improvement in diabetes care and outcomes. Research is under way to “close the loop” with continuous glucose monitors enabled to stop insulin delivery in pumps to reverse nocturnal hypoglycemia.

A more detailed summary of research at the Center can be obtained by consulting the Barbara Davis Center's Web site at www.barbaradaviscenter.org.

Dr. H. Peter Chase’s research interests are in continuous glucose monitoring (CGM) in children with type 1 diabetes. He is also working on the “closed-loop (CGM → Insulin Pump) pancreas.” He is a co-principal investigator in the Type 1 Diabetes/TrialNet diabetes prevention study.

Dr. Howard Davidson is studying mouse and human T-cells. His research is focused on using a variety of molecular biological techniques on a day to day basis in studies of B and T cell autoimmunity to pancreatic beta cell proteins.

Dr. George Eisenbarth’s research interests include understanding the basic immunology underlying the pathogenesis of type 1 diabetes, specifically the MHC (Major HistoCompatibility) peptides-T cell interactions that lead to disease. He is interested in studying the pathogenesis, prediction, and prevention of type 1 diabetes mellitus, including studies of the immunogenetics of type 1 diabetes, focusing on the activation and natural history of specific patterns of autoimmunity in genetically susceptible individuals. His basic studies include investigation of autoimmunity in the NOD mouse model of type 1 diabetes, including anti-insulin autoantibodies and anti-insulin islet-infiltrating T cells that have a shared T cell receptor Alpha chain motif.

Dr. Pamela Fain’s research focuses on the genetics of type 1 diabetes and vitiligo and their association with other autoimmune diseases, with a special interest in the population genetics of the HLA system. Specific projects include genome-wide association studies of vitiligo and twin studies of type 1 diabetes.

Dr. Rosanna Fiallo-Scharer’s interests include research in continuous glucose monitoring (CGM) in children with type 1 diabetes.

Dr. Satish Garg and his research team are very active with several clinical research studies that include investigating continuous glucose monitoring systems, newer insulins, and enhancing Type 1 diabetes care with adjunctive therapeutics.

Dr. Roberto Gianani’s main focus of his laboratory is the study of islet development and the pathology of the pancreas in individuals with diabetes, islet autoimmunity or chronic pancreatitis. His laboratory recently developed a transgenic NOD mouse expressing the apoptosis inhibitor survivin under the Rat Insulin Promoter (RIP – Survivin transgenic mice) with the aim of investigating the role of developmental islet apoptosis in the pathogenesis of Type I diabetes. Recent studies performed in his laboratory on aged normoglycemic have revealed ectopic islet ß-cell production in liver in the absence of normal islets in the pancreas.

Dr. Peter Gottlieb and his research staff are working on projects in new onset type 1 diabetes subjects. One of the research models is looking at how new medications could suppress/modulate the immune system to potentially slow or alter the progression of type 1 diabetes.

Dr. Dirk Homann’s research interests lie in the areas of autoimmunity, immunological memory, and persistent viral infections. The common theme among these topics is a focus on T cell immunity under conditions where specific T cells may cause pathology (autoimmunity), provide protection upon reencounter with a pathogen (immunological memory), or are impaired in their capacity to control an infection (persistent virus infections).

Dr. John Hutton’s research focuses on the molecular cell biology of insulin secretion and the role of secretory granule proteins in the pathogenesis of type 1 and 2 diabetes. Current studies include the roles of the newly discovered zinc transporter, SLC30A8, the newly discovered type 1 diabetes autoantigen, ZnT8, a pancreatic beta cell-specific zinc transporter, and islet glucose 6 phosphatase G6PC2 as autoantigens in type 1 diabetes and the development of novel antigen-based therapeutic approaches to the prevention of the disease. His lab also studies the cellular biology of the beta cell and the role of the SLC30A8 in the transport of cellular zinc and the secretion of insulin, and the functional divergence, if any, of a tryptophan to arginine single nucleotide polymorphism in the carboxyl terminus of ZnT8 shown to confer susceptibility to type 2 diabetes Dr. Hutton is the Director of the UCSOM Diabetes and Endocrine Research Center (DERC) and the BDC JDRF Autoimmunity Prevention Center.

Dr. Georgeanna Klingensmith is studying the chronic complications of diabetes and their prevention. She also heads the fellowship program at the Barbara Davis Center, which seeks to mentor and develop young scientists to pursue careers in diabetes research.

Dr. David Maahs is studying the complications of diabetes and their prevention, especially cardiovascular and renal complications.

Dr. Aaron Michels’ research focuses on understanding the basic immunology of type 1 diabetes, with a goal of understanding the trimolecular complex (MHC – peptide – T cell receptor) to design therapeutics to prevent and stop the autoimmune progression of beta cell destruction. One major focus is on the use of small molecules, designed to be therapeutic agents, to stimulate and inhibit T cell responses. A second component to his research involves clinical trials using medications to alter the immune system to prevent and treat type 1 diabetes. The ultimate goal is to stop the immune system from destroying insulin producing cells.

Dr. Maki Nakayama's research is focused on autoantigens that are primarily targeted by autoreactive T cells and may be essential to cause type 1 diabetes. An insulin peptide (B:9-23) is essential to initiate type 1 diabetes in the NOD mouse model, and there exists a specific T cell receptor (TCR) sequence that reacts with B:9-23. Targeting/blocking such TCR may be potential immunotherapies for human type 1 diabetes. Dr. Nakayama's group is currently exploring such critical human TCR sequences by directly approaching pancreatic islets of patients having type 1 diabetes. Her future goals are to develop antigen-specific immunotherapies by targeting T cells expressing such pathogenic TCRs and to seek primary antigens for human type 1 diabetes.

Dr. Marian Rewers’ primary research has been in the area of epidemiology/etiology of type 1 diabetes as well as insulin resistance and cardiovascular complications of both type 1 and 2 diabetes. Dr. Rewers is the principal investigator of four large NIH-funded projects: the Diabetes Autoimmunity Study in the Young (DAISY), The Environmental Determinants of Diabetes in the Young (TEDDY), the Coronary Artery Calcification in Type 1 Study (CACTI), and the Genetic and Environmental Causes of Celiac Disease.

Dr. Suparna Sarkar’s research interests are in beta cell neogenesis, regeneration and death.

Dr. Robert Slover’s primary focus is in research leading to the development of a “mechanical pancreas.” This clinical research area includes the use of continuous glucose monitors, insulin pump delivery systems, and the development of algorithms that allow a "closed loop system" for the management of diabetes.

Dr. Andrea Steck’s research interests are in the area of the genetics, epidemiology and prediction of type 1 diabetes. She is also involved in type 1 diabetes prevention trials and studies looking at preservation of C-peptide over time in type 1 diabetes.

Dr. Janet Wenzlau focuses on the analysis of humoral autoimmune responses in T1D. Her projects include epitope identification, assay development, and mechanisms of disease progression.

Dr. R. Paul Wadwa studies the complications of diabetes and their prevention, with special emphasis on cardiovascular and renal complications. Dr. Wadwa also has an interest in clinical trials for new technologies and new medications for the management of diabetes.

Dr. Phillippe Walraven’s research interests include research in continuous glucose monitoring (CGM) in children with type 1 diabetes and the prediction and prevention of type 1 diabetes.

Dr. Danny Zipris’ research interests include understanding the mechanisms by which virus infection triggers autoimmune diabetes in rat models of the disease. Another major interest is identifying the role of the innate immune system and TLR (Toll-Like Receptor) signaling pathways in the course of diabetes in genetically susceptible individuals and animal models.