Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease characterized by selective destruction of the insulin secreting ?-cells found in pancreatic islets of Langerhans. While ?-cell destruction is mediated by T-lymphocytes-dependent mechanisms, the pathways that initiate this autoimmune attack are unknown. The low concordance rate for diabetes development among identical twins (less than 40%) indicates that environmental factors, in addition to genetic predisposition, participate in the induction of autoimmune diabetes. Viral infection is one environmental factor that has been proposed to initiate ?-cell damage during the development of diabetes. The broad goals of this research are to elucidate the biochemical mechanisms by which virus infection contributes to the loss of ?-cell function and viability during diabetes development. Using a virus known to induce diabetes in susceptible mice (Encephalomyocarditis virus, EMCV), we have identified a novel antiviral response that is characterized by the expression of inflammatory genes (inducible nitric oxide synthase, iNOS and interleukin (IL)-1) that are known to damage ?-cells. This inflammatory response is regulated by the CC chemokine receptor Ccr5, and functions to attenuate virus replication. The inflammatory response does not require TLR3 or mda5, two double-stranded RNA sensors known to regulate the production of type 1 IFN. This application will test the hypothesis that the early inflammatory response contributes to virusinduced diabetes through Ccr5 signaling in macrophages or aberrant regulation of Ccr5 expression by ?-cells. There are three specific aims: 1) To test the hypothesis that Ccr5 controls the macrophage response to EMCV infection through G-protein coupled receptor-activated signaling cascades that regulate both transcription and translation of inflammatory genes. 2) To test the hypothesis that CCR5-deficiency will attenuate diabetes development in response to EMCV infection in genetically susceptible mice. 3) To test the hypothesis that aberrant expression of CCR5 in ?-cells increases the susceptibility of these cells to damage and the induction of diabetes in response to virus infection. A number of biochemical, molecular, immunological, histochemical, and transgenic techniques will be utilized to investigate the cellular pathways through which viral infection stimulates macrophage activation and modulates ?-cell function and viability. It is hoped that insights into regulation of macrophage and ?-cell responses to virus infection gained from these proposedstudies will influence the design of therapeutic strategies aimed at the prevention of this debilitating disease.

Public Health Relevance

Autoimmune, or insulin-dependent diabetes mellitus, is characterized by an inflammatory reaction in and around pancreatic islets, followed by selective destruction of -cells. The broad goals of this research are to elucidate the initiation or triggerng events that induce autoimmune diabetes. Virus infection is one environmental agent that has been suggested to cause diabetes. In this application, a mouse model will be generated to explore the role of virus infection in the induction of autoimmune diabetes. Also, the signaling pathways that are responsible for -cell damage will be elucidated with the hope that we will identify potential therapeutic targets to develop new approaches aimed at attenuating -cell damage and the development of autoimmune diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI044458-15
Application #
8725882
Study Section
Special Emphasis Panel (ZRG1-CADO-Q (08))
Program Officer
Bourcier, Katarzyna
Project Start
1998-09-30
Project End
2019-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
15
Fiscal Year
2014
Total Cost
$382,500
Indirect Cost
$132,500
Name
Medical College of Wisconsin
Department
Biochemistry
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
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