Abstract

Foremost among the animal models of human insulin-dependent diabetes mellitus is the BB rat. These animals abruptly become ketoacidotic, experience complete destruction of pancreatic beta cells, and requier exogenous insulin administration for survival. A number of studies suggest that this model of diabetes has an autoimmune pathogenesis. To test the hypothesis that spontaneous diabetes in the BB rat results from a failure of autoregulation within the immune system, we plan to conduct experiments designed either to induce or prevent diabetes. We plan first to isolate and to identify the cell or cells that destroy pancreatic beta cells in this animal. In addition, the cellular mechanism by which this destruction takes place will be studied. We will attempt to purify and characterize the soluble cellular products that mediate beta cell destruction. The microenvironmental factors and specific characteristics of the target beta cells of BB rats that render this animal susceptible to diabetes will also be examined. In experiments complementary to those designed to elucidate the mechanism of induction, we will attempt to identify the various cell(s) and/or cellular products responsible for prevention of diabetes in this animal. Advanced technology diffusion chambers will play an important role in these studies. We also intend to study BB islet physiology in vitro. We will use the method of isolated perfusion of the pancreas to quantitate insulin secretion. With this mehtod we can trace important pathophysiological events as they ocur during the development of spontaneous diabetes. Additionally, we will be able to perfuse the isolated pancreas with cells and cell products involved in the induction of diabetes. Our long range goal is to achieve the ability to induce and prevent diabetes in a predictable manner in the BB rat. These experiments should allow us to assess the validity of the original hypothesis that insulin dependent diabetes mellitus results from an immunoregulatory defect.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK025306-12
Application #
3483451
Study Section
Metabolism Study Section (MET)
Project Start
1978-09-01
Project End
1991-08-31
Budget Start
1989-09-01
Budget End
1990-08-31
Support Year
12
Fiscal Year
1989
Total Cost
Indirect Cost

  Institution

Name
University of Massachusetts Medical School Worcester
Department
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655

  Publications

Tirabassi, Rebecca S; Guberski, Dennis L; Blankenhorn, Elizabeth P et al. (2010) Infection with viruses from several families triggers autoimmune diabetes in LEW*1WR1 rats: prevention of diabetes by maternal immunization. Diabetes 59:110-8
Jurczyk, Agata; Pino, Steven C; O'Sullivan-Murphy, Bryan et al. (2010) A novel role for the centrosomal protein, pericentrin, in regulation of insulin secretory vesicle docking in mouse pancreatic beta-cells. PLoS One 5:e11812
Mordes, John P; Cort, Laura; Norowski, Elaine et al. (2009) Analysis of the rat Iddm14 diabetes susceptibility locus in multiple rat strains: identification of a susceptibility haplotype in the Tcrb-V locus. Mamm Genome 20:162-9
Chopra, Prerna; Diiorio, Philip; Pino, Steven C et al. (2009) Failure of alpha-galactosylceramide to prevent diabetes in virus-inducible models of type 1 diabetes in the rat. In Vivo 23:195-201
Pino, Steven C; O'Sullivan-Murphy, Bryan; Lidstone, Erich A et al. (2009) CHOP mediates endoplasmic reticulum stress-induced apoptosis in Gimap5-deficient T cells. PLoS One 4:e5468
Blankenhorn, Elizabeth P; Cort, Laura; Greiner, Dale L et al. (2009) Virus-induced autoimmune diabetes in the LEW.1WR1 rat requires Iddm14 and a genetic locus proximal to the major histocompatibility complex. Diabetes 58:2930-8
Pino, Steven C; O'Sullivan-Murphy, Bryan; Lidstone, Erich A et al. (2008) Protein kinase C signaling during T cell activation induces the endoplasmic reticulum stress response. Cell Stress Chaperones 13:421-34
Zipris, Danny; Lien, Egil; Nair, Anjali et al. (2007) TLR9-signaling pathways are involved in Kilham rat virus-induced autoimmune diabetes in the biobreeding diabetes-resistant rat. J Immunol 178:693-701
Blankenhorn, Elizabeth P; Descipio, Cheryl; Rodemich, Lucy et al. (2007) Refinement of the Iddm4 diabetes susceptibility locus reveals TCRVbeta4 as a candidate gene. Ann N Y Acad Sci 1103:128-31
Morrison, Alan R; Moss, Joel; Stevens, Linda A et al. (2006) ART2, a T cell surface mono-ADP-ribosyltransferase, generates extracellular poly(ADP-ribose). J Biol Chem 281:33363-72

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