SUMMARY A central component of diabetes pathogenesis is dysregulated secretion of insulin and glucagon from b and α cells of the endocrine pancreas. Endocrine cells rely on protein quality control (QC) systems within the endoplasmic reticulum (ER) to clear misfolded proteins, maintain ER homeostasis and ensure hormone production. Misfolded proteins are removed in part through substrate-specific clearance by Sel1L-Hrd1 ER- associated degradation (ERAD), or bulk degradation of aggregates by autophagy. Our recent study showed that ERAD and autophagy regulate different aspects of β cell biology – maintenance of β cell identity and survival, respectively. Despite their shared importance in controlling glucose homeostasis, our understanding of α cell biology lags behind that of β cells. The mechanisms regulating ER homeostasis in (and thus, synthetic capacity of) α cells remain largely unexplored. To this end, mouse models lacking Sel1L-Hrd1 ERAD or autophagy in α cells were characterized. Defective ERAD limited glucagon production and α cell mass, but did not impair systemic glucagon secretion in response to hypoglycemia. In contrast, defective autophagy in α cells disrupted ER homeostasis and impaired glucagon secretion in vivo. Intriguingly, our preliminary data points to potential crosstalk between these two QC machineries. Hence, this proposal will test the overarching hypothesis that Sel1L-Hrd1 ERAD and autophagy cooperate to ensure ER proteostasis in pancreatic α cells – which is critical for α cell identity, function and/or survival. Using a combination of in vivo and in vitro genetic and pharmacologic approaches using mouse models, cell lines, and human islets, we will test the following Aims: (1) Demonstrate the pathophysiological importance of the interplay between ERAD and autophagy in α cells, and (2) Delineate the molecular mechanism underlying the crosstalk between ERAD and autophagy in α cells. This study will provide unprecedented insights into ER QC mechanisms in α cells, which may be harnessed to identify new therapeutic approaches to address α cell dysfunction in diabetes. This undertaking will build upon Dr. Reinert’s scientific expertise in developmental biology and physiology with training in two cutting-edge cell biology fields, ERAD and autophagy, with a focus on organelle crosstalk. Moreover, this study will strengthen Dr. Reinert’s technical skills by providing training in state-of-the-art cell biology techniques, thus paving a strong foundation for her future career as a physician scientist leading an interdisciplinary team studying islet cell biology and pathophysiology. This career development award will be overseen by three outstanding scientists and mentors Drs. Ling Qi, Peter Arvan, and Jiandie Lin at the University of Michigan.