Autoimmune diabetes is characterized by an inflammatory reaction in and around pancreatic islets, followed by selective destruction of beta-cells. The broad goals of this research are to elucidate the cellular mechanisms associated with pancreatic beta-cell destruction and identify mechanisms by which beta-cells protect themselves against cytokine- and free radical-mediated damage. We have shown that nitric oxide mediates the inhibitory actions of interleukin-1 (IL-1) and interferon-gamma (IFN-gamma) on beta-cell function. Nitric oxide also activates a """"""""recovery"""""""" pathway that protects beta-cells from cytokine-mediated damage. It is this delicate balance between the toxic and protective actions of nitric oxide that may ultimately determine the susceptibility of beta-cells to cytokine-mediated damage. This proposal focuses on elucidating the cellular pathways of beta-cell destruction and recovery from cytokine-mediated damage. There are three specific aims. 1. To elucidate the biochemical mechanisms by which resident macrophage activation and proinflammatory cytokine release in islets mediates beta-cell damage. Experiments proposed will use a transgenic approach to determine the role of the IL-1a converting enzyme (ICE), the IL-1 receptor, and IL-1 receptor signaling components in mediating beta- cell damage stimulated by the local production of IL-1 by macrophages in the microenvironment of the islet. 2. To test the hypothesis that nitric oxide and peroxisome proliferator-activated receptor (PPAR)-gamma, agonists activate a pathway(s) that protects beta-cells from cytokine-mediated damage. Proposed experiments will examine the mechanisms by which nitric oxide and PPAR-gamma agonists prevent cytokine-mediated beta-cell damage. 3. To use expression profiling to identify candidate genes with altered expression under conditions associated with beta-cell recovery from cytokine-mediated damage. Once identified, these genes or gene products will be expressed or transduced into beta-cells to determine the mechanisms of protection from cytokine-mediated damage. A number of biochemical, molecular biological, immunological, histochemical, and transgenic techniques will be utilized to investigate the cellular pathways through which nitric oxide mediates beta-cell destruction and the pathways that participate in the protection of beta-cells from cytokine-mediated damage. It is hoped that insights into the mechanisms of cytokine-mediated damage and protection from this damage gained from these studies will influence the design of therapeutic strategies aimed at the prevention or treatment of this debilitating disorder.
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