Role of Pancreatic Elastase in Beta Cell Health, Autoimmunity and Type 1 Diabetes - PROJECT SUMMARY/ABSTRACT: The exocrine (e.g., acinar cell) and endocrine (e.g., islet b-cell) compartments of the pancreas have long been considered functionally distinct. However, there is now overwhelming evidence for exocrine-endocrine crosstalk in the development, physiology, and dysfunction of the pancreas. For example, pancreas size (99% of which is exocrine tissue) is significantly reduced at type 1 diabetes (T1D) onset, in islet autoantibody-positive donors without diabetes, and in first degree relatives of T1D patients elements for exocrine-specific digestive enzymes pathogenesis, but mechanisms remain unknown. In response to RFA-DK-23-007, our Team brings deep . Multiple T1D risk variants map to cis- regulatory . These findings implicate the exocrine pancreas in T1D expertise in the biology, immunology and imaging of the exocrine/endocrine pancreas to unravel the molecular crosstalk among these cellular compartments in b-cell health and immunity. Our Team recently discovered that unregulated pancreatic elastase activity from acinar cells has detrimental effects on b-cell biology and immunity. Mechanistically, we have evidence that elevated pancreatic elastase proteolytically inactivates a cell surface growth receptor on b-cells to trigger a signaling cascade that halts proliferation, increases inflammatory cytokines, and leads to cell death. Furthermore, our Team discovered a missense mutation in pancreatic elastase that increases its expression and is linked to an inherited syndrome of pancreatitis, diabetes and pancreatic ductal adenocarcinoma. In parallel, we have identified small molecules that inhibit pancreatic elastase expression or activity, increase regulatory T-cell numbers in vivo, and promote murine and human b-cell health to prevent diabetes in mice. Taken together, our preliminary data support the over-arching hypothesis that elevated pancreatic elastase activity is directly pathogenic to islet b-cells in part through impairing growth signaling to induce secretion of inflammatory cytokines, autoimmunity and cell death; and that attenuating elastase activity will promote b-cell health and protect against T1D. Building upon these results, the goals of this project are to determine the human T1D relevance of the pancreatic elastase signaling circuit by defining how it: (1) predicts T1D risk in patients, (2) triggers inflammation and autoimmunity, and (3) can be effectively targeted to prevent and/or reverse T1D. These studies will provide insights into the mechanisms responsible for pancreatic exocrine-endocrine crosstalk in T1D by understanding how pancreatic elastase impacts human b-cell health and autoimmunity, and test new pharmacologic approaches to limit elastase activity as a novel therapeutic strategy for T1D.