The overall goal of this program project is to understand the immunopathogenesis of insulin-dependent diabetes mellitus (IDDM) at the cellular and molecular level. The program involves a collaborative interaction between members of four departments organized into projects supported by four core facilities. Expertise in immunology, molecular biology, cell biology and clinical and experimental studies of diabetes will be focused on the problem of the primary lesion in IDDM, the destruction of the pancreatic beta cell. The role of T lymphocytes, of cytokins, and of MHC molecules in this process will be analyzed, using a wide range of techniques. Specifically, we will address the following questions: What analyzed, using a wide range of techniques. Specifically, we will address the following questions: What are the autoantigens recognized by T cells on the beta cell? What receptors are involved in this recognition event? What regulates the activation of autoreactive T cells? How are the beta cells destroyed? What role do inflammatory cytokins play in the inductive and effector phases of beta cell destruction? What role does glucose metabolism play in susceptibility of beta cells to autoimmune attack? These questions will be addressed by collaborative interactions between the principal investigators of the four projects, which are as follows: Project 1, C. Janeway, PI: Using cloned, diabetogenic T cell lines, the nature of the T cell receptors and their beta cell ligands will be determined, and the role of beta cells in stimulating autoimmunity determined. Project 2, A. Hayday, PI: The nature of the T cell receptor genes involved in autoimmune diabetes and their impact on T cell receptor transgenic mice will be determined. Project 3: R. Flavell, PI: The effect of MHC and cytokine genes under rat insulin promoter on beta cell function and induction of autoimmunity will be determined. Project 4: R. Sherwin, PI. The mechanisms of beta cell destruction by T cells and the influence of glucose on beta cell susceptibility to autoimmune attack and induction of response will be determined. These four projects will be supported by an administrative core to coordinate the project as a whole, a NOD mouse colony critical to the in vivo experimentation in most projects, a laboratory for rodent islet isolation essential to most of the studies, and an immunocytochemistry facility to allow us to accurately assess immunopathology of beta cell destruction in vivo and vitro. The program is coordinate by frequent meetings of the program faculty, bridging the various departments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK043078-02
Application #
3095656
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1990-09-01
Project End
1995-02-28
Budget Start
1991-06-01
Budget End
1992-02-29
Support Year
2
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Wong, F S; Visintin, I; Wen, L et al. (1998) The role of lymphocyte subsets in accelerated diabetes in nonobese diabetic-rat insulin promoter-B7-1 (NOD-RIP-B7-1) mice. J Exp Med 187:1985-93
Zekzer, D; Wong, F S; Ayalon, O et al. (1998) GAD-reactive CD4+ Th1 cells induce diabetes in NOD/SCID mice. J Clin Invest 101:68-73
Zekzer, D; Wong, F S; Wen, L et al. (1997) Inhibition of diabetes by an insulin-reactive CD4 T-cell clone in the nonobese diabetic mouse. Diabetes 46:1124-32
Grewal, I S; Flavell, R A (1997) New insights into insulin dependent diabetes mellitus from studies with transgenic mouse models. Lab Invest 76:3-10
Wong, F S; Visintin, I; Wen, L et al. (1996) CD8 T cell clones from young nonobese diabetic (NOD) islets can transfer rapid onset of diabetes in NOD mice in the absence of CD4 cells. J Exp Med 183:67-76
Kraszewski, K; Daniell, L; Mundigl, O et al. (1996) Mobility of synaptic vesicles in nerve endings monitored by recovery from photobleaching of synaptic vesicle-associated fluorescence. J Neurosci 16:5905-13
Takei, K; Mundigl, O; Daniell, L et al. (1996) The synaptic vesicle cycle: a single vesicle budding step involving clathrin and dynamin. J Cell Biol 133:1237-50
Coulombe, M; Yang, H; Guerder, S et al. (1996) Tissue immunogenicity: the role of MHC antigen and the lymphocyte costimulator B7-1. J Immunol 157:4790-5
Guerder, S; Flavell, R A (1995) Costimulation in tolerance and autoimmunity. Int Rev Immunol 13:135-46
Dirkx Jr, R; Thomas, A; Li, L et al. (1995) Targeting of the 67-kDa isoform of glutamic acid decarboxylase to intracellular organelles is mediated by its interaction with the NH2-terminal region of the 65-kDa isoform of glutamic acid decarboxylase. J Biol Chem 270:2241-6

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