Mechanism of PANDER Induced Apoptosis

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DESCRIPTION (provided by applicant): Pancreatic Derived Factor (PANDER) is a recently identified pancreas-specific 235 amino acid protein with a secretion signal peptide. PANDER message is dominantly expressed in the islets of Langerhans of the pancreas, and to a lesser extent in the small intestine and prostate. Based on conserved cytokine secondary structures, PANDER was identified and predicted to be a novel, pancreas-specific cytokine. Additional studies revealed exogenously added and adenoviral delivered intracellular PANDER is capable of inducing apoptosis of primary islets and various islet cell lines. Similar to PANDER'S biological effects on islets, various inflammatory cytokines such as interleukin-1(, tumor necrosis factor-(, and interferon-( can promote cell death via apoptosis and necrosis. However, the precise mechanisms initiating (-cell death in autoimmune diabetes have yet to be determined and PANDER may be potentially involved. In addition, due to the recent discovery of PANDER the function is still unknown. The hypothesis behind the proposed research is that the cytokine induced upregulation of PANDER within islets downregulates the antiapoptotic protein of p21 and concordantly increases caspase-3 expression which subsequently induces islet cell apoptosis and impacts the pathogenesis of type I diabetes. The two major goals are: (1) identify the mechanism of cytokine regulated PANDER induced islet apoptosis; and (2) determine the role of PANDER in the pathogenesis of type I diabetes, with four specific aims: Aim 1: Determine if cytokines upregulate endogenous and secreted PANDER in murine islets. Aim 2: Characterize the effects of downregulation of PANDER expression on cytokine induced islet apoptosis. Aim 3: Elucidate the PANDER induced apoptotic signaling pathways by focusing on the roles of candidate genes and the PANDER receptor. Aim 4: Evaluate the role of overexpression in a mouse model with regard to induction of a diabetic phenotype. Relevance- Diabetes is currently a serious and rapidly growing healthcare problem impacting approximately 18 million people in the United States. A type of diabetes known as type 1 diabetes results in the destruction of insulin-producing islet cells. The exact mechanism of islet-cell destruction is unknown and our grant identifies the role of a novel islet-produced molecule known as PANDER in this destructive process.