Research Theme 1
Immunopathogenesis and Genetics of Diabetes
Professor of Transplant Surgery
Director UVA Human Islet Isolation Facility
Dr. Brayman directs the UVA Human Islet Transplantation Program. He was recruited from the University of Pennsylvania where he had assisted in the development of their human islet transplantation facility. Over the past four years he has built a successful human islet transplantation activity. This has included establishing the university's first FDA approved GMP-tissue isolation facility for clinical transplantation. The Human islet isolation facility is separate from our DERC islet isolation facility. However, we has established a working agreement whereby human islets not destined for transplantation but isolated by the Human Islet Facility can be used for research purposes (see Islet Core). Dr. Brayman's research deals with factors which affect clinical responses to islet transplantation and development of new methods for assessment of islet viability following isolation.
Professor of Biochemistry & Molecular Genetics
Research focus: Genetics of type 1 diabetes
Type 1 diabetes (T1D) arises from the actions, and possible interactions, of multiple genetic and environmental risk factors. The goal of Dr. Concannon’s research is to dissect the genetic components of T1D risk through linkage and association studies carried out in simplex and multiplex T1D families. They are focusing specifically on regions on chromosomes 10 and 16 that have consistently displayed evidence of linkage to T1D in prior studies. Within these regions they are testing single nucleotide polymorphism markers for disease association and evaluating potential candidate genes. In addition to searching for novel T1D genetic risk factors, they are characterizing the functional consequences of known T1D-associated variants, such as those occurring in the PTPN22 gene, in human T1D patients and controls.
Professor of Microbiology
This laboratory has developed techniques for the isolation and characterization of the complex mixture of peptides bound to MHC molecules, and is analyzing the peptides expressed in normal, virus-infected, and tumor cells. These studies have allowed them to define the specific peptides that are recognized during immune reactions to human tumor cells and tissue transplants. The peptides are now being used to develop therapeutic vaccines for melanoma, and other strategies to control transplant rejection. We are also studying the mechanisms by which peptides are produced from the proteins that are made in cells.
Kevin R. Lynch
Professor of Pharmacology
Research focus: Sphingosine 1-phosphate Signaling and Autoimmune Diabetes
Dr. Lynch’s group and others have documented that sphingosine 1-phosphate (S1P) receptor agonists, specifically the immunomodulatory investigational drug FTY720, prevent diabetes in the NOD mouse. Although such drugs can hold frank disease at bay for at least six months, the disease progression resumes unabated when the drug is withdrawn. We wish to learn whether other S1P drugs, perhaps in combination with additional agents, can delay or even prevent the appearance of diabetes in the NOD mouse after S1P drug withdrawal. To accomplish this goal, we use both chemical biology and genetic approaches. We have a series of proprietary FTY720-like compounds (different S1P receptor type selectivity, antagonists, etc.) and are using these to determine what receptor types must be activated to prevent diabetes in the NOD mouse and to learn whether interdicting early in the disease process can delay emergence of diabetes post drug regimen.
We are investigating other applications of our S1P compounds in collaboration with Dr. K. Brayman, for example stabilization of pancreatic islet cultures ex vivo and islet transplantation. Regarding genetic tools, we have imported recently the BDC2.5 transgenic mouse, which provides a simplified model of autoimmune diabetes. When this transgene is placed in the context of H2-g-7 major histocompatiblity antigen on a C57BL/6 background, insulitus proceeds at an accelerated pace (compared to the NOD mouse). One of the B6 loci associated with aggressive progression of disease includes the sphingosine kinase type 2 (Sphk2) gene. We have our SPHK2 null mouse congenic with B6, which affords us the opportunity to determine whether the lack of SPHK2 will influence the progression of disease in the BDC2.5 x B6.H2-g-7 mice. This work was supported initially by a Pilot and Feasibility grant from the UVA DERC; data from those studies was used to obtain a regular research grant from the JDRF. Finally, the “speed congenic” service of the DERC were used to make the SPHK2 mice congenic on the B6 background in five generations.
Professor of Microbiology
Director DERC Genetics Core
Research focus: Genetic studies of diabetes susceptibility in the NOD mouse
Having identified six separate non-MHC genes that determine diabetes-susceptibility in the NOD mouse, Dr. McDuffie is characterizing and cloning these genes. Members of her laboratory are studying their specific roles in the diabetogenic process using tissue transfers in vivo, as well as assays of T lymphocyte function and pancreatic islet development in vivo and in vitro. Collaborations with D. Wotton (Biochemistry), J. S-S. Sung (Medicine/Rheumatology), and T. L. Macdonald (Chemistry) at the University of Virginia, X. She at the Medical College of Georgia, and the M. Clare-Salzler/S. Litherland laboratories at the University of Florida at Gainesville have established strong candidate genes for 3 of these loci and support ongoing efforts to determine the mechanisms underlying their effects. Using the new DNA and data repositories funded through the Type 1 Diabetes Genetics Consortium and collaborations with S. S. Rich, M. M. Sale, and J. Mychaleckyj (newly recruited to the University of Virginia), we are performing detailed association and linkage analyses to determine whether these strong candidate genes identified in NOD mice also play a role in human susceptibility to Type 1 diabetes.
Craig S. Nunemaker
Assistant Professor of Research
Director, Pancreatic Islet and Cell Core Facility
Research focus: Pancreatic beta-cell and islet physiology
The long-term goal of Dr. Nunemaker's Lab is to determine the mechanisms of inflammatory-mediated pancreatic islet dysfunction related to diabetes and metabolic disorders. Inflammation and immune responses can lead to destruction of insulin-producing beta cells within islets through the effects of exogenous cytokines or through induction of certain cytokines within the beta cells themselves. Dr. Nunemaker's Lab has shown that pro-inflammatory cytokines induce dysfunction in islet handling of intracellular calcium at much lower concentrations than required to measurably disrupt insulin secretion and induce cell death. Possible source(s) of dysfunctional calcium handling are being investigated including endoplasmic reticulum stress, mitochondrial disruption, and ion-channel dysfunction using a combination of physiological and molecular approaches. By identifying the physiological impact of cytokines at very low doses, they hope to identify early and reversible steps in islet dysfunction.
Dr. Nunemaker's Lab is also focused on developing techniques to assess and improve islet health and function. One project, funded by the Mouse Metabolic Phenotyping Center, involves pre-labeling one set of islets with an inert fluorescent dye to allow simultaneous comparisons of labeled and unlabeled islets under identical conditions. This approach will provide valuable and novel information about dynamic changes in islet metabolic rates, calcium handling, and secretion in response to glucose or other stimuli in order to detect very precise deficiencies or enhancements in islet function. This technique will be used to identify precursors of islet dysfunction and to assess potential therapies for diabetes at the islet level.
Stephen S. Rich
Professor of Public Health Sciences
Director Center for Population Genetics
Research focus: Identification of candidate genes for type 1 and type 2 diabetes
Dr. Rich's research is centered on understanding the genetic epidemiology of diabetes and its complications. These studies range from estimating the familial aggregation of disease and subclinical markers of disease within families, to gene mapping, and to gene discovery. These studies have focused on both type 1 diabetes and type 2 diabetes, and the complications of these forms of diabetes, particularly atherosclerosis, stroke, and nephropathy. As PI of the Type 1 Diabetes Genetics Consortium, his research uses genome-wide linkage scans, evaluation of candidate genes, intensive examination of the MHC region, and genome-wide association scans to better understand the genetic basis of type 1 diabetes. In collaboration with investigators at Wake Forest University and the Joslin Diabetes Center, they have been exploring the genetic basis of type 2 diabetes in Caucasian pedigrees and African-American families. Their work in the genetics of diabetic nephropathy ranges from genome-wide linkage scans (Wake Forest, Joslin), candidate gene evaluation (Wake Forest, Joslin, Minnesota), and examination of mRNA expression differences in those with fast versus slow progression (Minnesota, Dartmouth).
Examination of the genetic contribution to stroke (with Mayo Clinic, Jacksonville) and atherosclerosis have primarily used an extensive examination of the candidate gene model, although genome-wide approaches are now being applied. Thus, the research program contributes to the immune pathogenesis of diabetes and its relationship to diabetes complications, aspects that are complementary to the mission and goals of the DERC.
Assistant Professor of Public Health Sciences
Research focus: Genetics of DM2 in African Americans
The prevalence of both type 2 diabetes and the complications of diabetes are 2-4 times greater in African-Americans than in Caucasian Americans. This laboratory carried out the first large-scale genome-wide scan for African-American type 2 diabetes using greater than 600 affected sib pairs from 250 families. The goal of her current work is to use a positional cloning approach to identify variants in genes that contribute to type 2 diabetes susceptibility in African-Americans. The laboratory is currently embarking on the construction of a dense SNP map to allow identification of haplotypes associated with type 2 diabetes in African-Americans followed by a focused search for genes contributing to diabetes.
Professor of Pathology
Research focus: Role of T-cells in the development of autoimmune polyendocrinopathy and type I diabetes
This laboratory explores the fundamental mechanisms of autoimmune disease prevention and induction based on new disease models that they developed (see above). Regulatory T cells bearing CD25 have the critical role of autoimmune disease prevention in normal adults. Their depletion leads to autoimmune disease that is triggered by endogenous antigens within 3 weeks. Interestingly, continuous endogenous antigenic stimulation is also required to maintain self-tolerance, perhaps by maintaining regulatory T cell function. Recently, his lab discovered that maternal autoantibody, nonpathogenic for adults, induces de novo pathogenic T cell response in their pups within the first five days of life, leading to severe neonatal autoimmune disease. Neonatal susceptibility to autoimmune disease is due to deficiency in the CD25+ regulatory T cells that develop after the CD25- effector T cells. This exciting finding supports a general conclusion of their research: Neonatal stimulation by antigen and environmental co-factors induce autoimmune disease rather than self-tolerance.