Grant: Project Grant

Acute pancreatitis (AP) causes high morbidity and mortality, and at considerable financial costs to health care in Canada. The most common cause of AP is alcohol, affecting 10% of alcoholics. There is still no effective specific treatment directed at the pathogenesis of alcoholic AP in part because the postulated disease mechanisms could not be directly tested on human pancreatic tissue. Glucagon-like peptide 1 (GLP-1)-based therapies, which potentiate glucose-mediated insulin secretion, is the new panacea for treating diabetes; now a multi-billion dollar pharmaceutical market. However, GLP-1 drug treatments exhibited six-fold increase in AP, the basis is totally unknown. Our overarching hypothesis is that alcohol and GLP-1 drugs can cause perturbations in autophagy, the cellular 'self-eating' process that normally gets rid of cellular garbage. Autophagy involves a series of vesicle formations that involve distinct SNARE proteins (Aim 1), which when pathologically activated (alcohol - Aim 2, GLP-1 - Aim 3), causes inadvertent protease activation (instead of physiologic degradation) which can damage and destroy acinar cells (i.e. AP). To mechanistically address these conditions in a clinically-relevant manner, we've developed the method of preparing fresh human pancreatic slices to assess autophagy processes and how their perturbations contribute to acinar cell injury. We will assess whether manipulation of autophagy SNAREs expression in rat pancreas can modify alcohol- and GLP-1-mediated pancreatic injury. This work may identify novel treatments for AP and impact current diabetes management in patients taking GLP-1 drugs.