Project Summary/Abstract Diabetes and its complications affect an ever-growing part of the global population. Recent studies point to beta cell defects as a common denominator in Type 1 and Type 2 diabetes. Here, we propose to interrogate the contribution of distinct coping mechanisms present in beta cells that serve to protect against physiological stress, but whose dysfunction can result in deterioration or destruction of beta cells under conditions of extended or unresolved stress. We focus on the connections between ER stress resulting in the unfolded protein response (UPR) and loss of beta cell identity caused by a novel regulator of beta cell identity. We propose to determine how these pathways interact and how they inform beta cell function. The proposed work is exclusively performed in human beta cells and takes advantage of our ability to generate and CRISPR- modify functional insulin producing cells from human stem cell populations. The overall goal of our proposed studies is to define the mechanisms resulting in beta cell dysfunction and subsequent diabetes, with a clear focus on identifying those signaling nodes that can be exploited for therapeutic intervention. We have assembled a team of leading experts on these specific cellular outcomes and have developed pharmacological and genetic tools to address how halting stress response in beta cells can alter the course of the disease. We pose that directly targeting stress response pathways in beta cells is an innovative and novel approach to diabetes treatment and prevention that also has implications for other degenerative diseases.