Autoimmune diabetes is characterized by the selective destruction of ?-cells that occurs during an inflammatory reaction in and around pancreatic islets. Inflammatory cytokines, released during this process, impair ?-cell function and can induce ?-cell death. Cytokines have also been implicated in the loss of functional ?-cell mass during the development of type 2 diabetes. The broad goals of this research are to elucidate the cellular mechanisms that are responsible the functional impairment and death of pancreatic ?-cell following cytokine treatment, and to identify pathways by which ?-cells protect themselves against cytokine-mediated damage. Reactive nitrogen species (RNS;e.g., nitric oxide) are primary mediators of the damaging actions of interleukin-1 (IL-1) and interferon (IFN)-??on ?-cell function and viability. We have shown that nitric oxide can also activate """"""""protective pathways"""""""" that lead to the recovery of insulin secretory function, mitochondrial oxidative metabolism, and the repair of damaged DNA. It is the delicate balance between the toxic and protective actions of RNS, produced by ?-cells in response to cytokines that ultimately determines whether these cells survive or die. This proposal will elucidate the pathways that control ?-cell fate following cytokine treatment. There are three specific aims: 1) To test the hypothesis that the response of ?-cells to cytokine treatment is determined by a) the form of reactive oxygen species (ROS) or reactive nitrogen species (RNS) produced, and b) the ability of ROS and RNS to selectively regulate signaling cascades that control cellular repair/protective pathways or activate cell death cascades;2) To test the hypothesis that Ataxia telangiectasia mutated (ATM) plays a primary role in regulating the response(s) of ?-cells to cytokine- and nitric oxide-mediated damage;3) To test the hypothesis that the activation status of SIRT1 determines whether ?-cells respond to cytokine treatment with the induction of """"""""protective pathways"""""""" or the stimulation of cell death cascades. A number of biochemical, molecular, immunological, cell biological and transgenic techniques will be utilized to investigate the cellular pathways through which nitric oxide and its reactive intermediates mediate ?-cell damage and the pathways that participate in the protection of ?-cells from cytokine-induced damage. It is hoped that insights into the mechanisms controlling the response of ?-cells to cytokines that are gained from these studies will influence the design of therapeutic strategies aimed at attenuating the loss of functional ?-cell mass during the development of diabetes.
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