Type 1 diabetes (T1D) is a childhood autoimmune disease in which insulin-producing beta cells are targeted and destroyed. This project builds on recent observations indicating that modification of self-proteins is a possible mechanism for acceleration of autoimmunity and progression to T1D. Our goal is to elucidate the mechanisms by which self-proteins are modified due to stress, how such modifications increase immune recognition, and whether responses to these proteins can serve as biomarkers of pathogenesis and targets for intervention. Our study will focus on the post-translational modification deamidation. Deamidation is the conversion of glutamine to glutamic acid or asparagine to aspartic acid, mediated by transglutaminase 2 (TGM2) enzymes (glutamine only) or spontaneously (glutamine and asparagine). First, we will optimize the detection of deamidation with mass spectrometry. Then, we will investigate the expression and activity of TGM2, the main enzyme responsible for deamidation, in the pancreas and thymus of NOD mice, a mouse model that spontaneously develops type 1 diabetes. Finally, we will investigate which peptides are deamidated in stressed human islets and if these peptides are immunogenic.
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