BLRD Research Career Scientist Award Application

Pancreatitis is a potentially fatal disease of exocrine pancreas, with significant morbidity and mortality, and a heavy burden on the US healthcare system. The disease is common in Veterans patient population. Its mechanism remains obscure, and no specific or effective treatment is available. Pancreatitis is not only associated with poor quality of life but is also a major risk factor for the deadly pancreatic cancer. The pancreatic acinar cell is a major participant in both acute and chronic pancreatitis. Its’ central physiologic function is to synthesize, transport, and secrete digestive enzymes. This is accomplished through coordinated actions of mitochondria, which provide energy (ATP); lysosomes and autophagy, mediating removal of damaged or dysfunctional organelles; and the endoplasmic reticulum (ER), a site of enzyme synthesis and folding. Several years ago we put forward a novel concept that Dysfunction of the pancreatic acinar cell organellar machinery mediating protein processing, trafficking, and degradation is central to the pathogenesis of acute pancreatitis. Our studies (as well as by other groups) have validated this hypothesis. These studies have been mostly performed within the framework of an NIH/NIDDK Program Project on which I serve as PD/PI – the first ever Program grant on pancreatitis, integrating the work of leading pancreatologists from 5 institutions across the US. We showed that both experimental and human pancreatitis are associated with profound disordering of acinar cell lysosomal, autophagy and mitochondrial pathways, and characterized the underlying mechanisms. We further showed that genetic and pharmacologic modulations of these pathways can ameliorate (or, conversely, cause) the disease. My current research provides further insight into these mechanisms. Studies supported by VA Merit award investigate the role of autophagy in chronic pancreatitis by using a novel, clinically relevant mouse model with pancreas-specific genetic insufficiency of the protein SPINK1 (mutations in which increase the risk of chronic pancreatitis in humans 20- to 40-fold). Studies supported by NIH/NIAAA and DOD investigate the role of organelle disorders in pancreatitis induced by environmental factors. The NIAAA-funded project examines the role of impaired lysosomal/autophagy pathway in the inflammatory response of alcoholic pancreatitis, and proposes new pharmacologic approaches. The DOD-funded project investigates the role of mitochondrial permeability transition pore (MPTP) in pancreatitis induced by combined action of alcohol and smoking, and analyzes the interrelations between mitochondrial dysfunction and ER stress. We apply pharmacologic and genetic approaches to examine beneficial effects of MPTP blockade in models of pancreatitis caused by alcohol and cigarette smoke. The focus of my most recent studies is on elucidating the mechanisms linking organellar disfunction to pancreatitis pathologies such as inflammation and cell death. We found, in particular, that lysosomal/autophagy dysfunction causes profound dysregulation of cholesterol metabolism in acinar cells, and that cholesterol-lowering drugs improve experimental pancreatitis. The findings are described in a manuscript now under revision in The Journal of Clinical Investigation; and I have submitted an R01 application to NIH to investigate the role of cholesterol dysregulation in the inflammatory and cell death responses of pancreatitis. Our studies have greatly advanced the knowledge of molecular mechanisms mediating pancreatitis, opened new research directions, and are recognized in the field as a paradigm shift.