Functional and molecular characterization of the human islet interferon alpha response

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PROJECT SUMMARY/ABSTRACT The incidence of diabetes in the US population has been rapidly increasing over the past several decades. Type 1 diabetes is a result of β-cell death, or apoptosis of the insulin-producing cells in the pancreas. However, we are currently limited in our understanding of the molecular events that are involved in the initiation of pancreatic β-cell apoptosis and on the role for β-cell heterogeneity in the pathogenesis of type 1 diabetes. Interferon (IFN)-α-mediated signaling is a key component of type 1 diabetes pathophysiology. Children genetically at risk for type 1 diabetes have a type I IFN-inducible transcriptional signature in blood cells that precedes appearance of autoantibodies. Type I IFN is also expressed in pancreatic islets from people with type 1 diabetes and laser-captured islets from living donors with recent onset type 1 diabetes show an increase in IFN-stimulated genes. IFN-α induces ER stress, insulitis, and a massive HLA class I overexpression in human β-cells, three hallmarks of type 1 diabetes. Collectively, these observations suggest a critical role for IFN-α signaling in the crosstalk between β-cells and the immune system in early type 1 diabetes. Using a xenograft model and live animal imaging studies, we recently made the novel observation that IFN-α stimulates a rapid accumulation of reactive oxygen species (ROS) within a subset of human β-cells. It is well established that β- cells are exquisitely sensitive to ROS accumulation, and a maladaptive response to ROS can lead to β-cell apoptosis. Therefore, we hypothesize that human β-cells exhibiting rapid ROS accumulation in response to IFN- α within the islet have a unique molecular signature that predisposes them to early apoptosis in T1D pathogenesis. To test this hypothesis, we will characterize the subset of cells exhibiting rapid accumulation of ROS in response to IFN-α exposure in vivo and determine whether these cells are selectively targeted for early apoptosis. The experiments outlined in the current proposal are specifically designed to identify and characterize some of the key early events associated with β-cell apoptosis in human islets, with the long-term goal of identifying novel therapeutic targets to prevent diabetes in the at-risk population.