Aurelia Lugea, PhD

Assistant Researcher, David Geffen School of Medicine at UCLA

The exocrine pancreas has the most extensive endoplasmic reticulum (ER) system of any tissue, in order to maintain a high rate of production, processing and secretion of proteins. Although disorders of ER function are thought to underlie alcohol toxicity, there is little information on precise detrimental effects of alcohol that cause ER dysfunction and promote its propagation into pathophysiologic features of pancreatitis including aberrant digestive enzyme activation and acinar cell death. The overall goal of Dr Lugea is to determine the pathologic biochemical events of alcohol abuse that impair ER function, protein folding and transit through the secretory pathway. Her recently developed mouse models of ER dysfunction in the exocrine pancreas combine chronic alcohol feeding with genetic attenuation of XBP1, a key element of the adaptive unfolded protein response that regulates ER homeostasis in pancreatic acinar cells. Dr Lugea hypothesizes that the disruption of the adaptive response in our mouse model of ER stress will reveal sensitizing pathologic effects of ethanol responsible for ER dysfunction, impaired protein synthesis and secretion that act as initial events triggering eventual widespread inflammation. Events downstream of ER dysfunction, including up-regulation of homeostatic autophagy to degrade misfolded proteins, likely contribute to the further propagation of ethanol-induced oxidative damage into pancreatitis. The advantages of her animal models, together with state-of-the art proteomic and metabolomic methodologies will facilitate identification of key proteins involved in maintaining ER function and cellular homeostasis in the exocrine pancreas during alcohol abuse. The use of these innovative techniques will help to identify many novel early steps in alcohol-induced pancreatic injury.