Pancreatic Regeneration from Alcohol-Associated Injury

University Of Texas Med Br Galveston, Galveston TX

Investigators

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Abstract

? DESCRIPTION (provided by applicant): The association between high alcohol intake and necroinflammatory diseases such as pancreatitis has been well documented for over 100 years. However, only 5% of heavy drinkers develop pancreatitis, implying the existence of adaptive mechanisms that restore pancreatic tissue following alcohol-associated injury. Remarkably, the mechanisms critical for pancreatic repair and regeneration following alcohol-associated injury are neither comprehensively analyzed nor fully understood. Thus this proposed research aims to characterize mechanisms important for the regeneration of pancreatic acinar cells, specialized secretory cells that are the primary target in alcoholic pancreatitis. Our preliminary studies highlight the importance of the Hepatocyte Growth Factor Receptor (MET) as an intrinsic survival and/or repair mechanism for acinar cells. Our studies show that MET signaling is low in normal adult pancreas. However, MET levels are elevated in ductal and acinar cells in human pancreatitis specimens, consistent with a role for MET as an adaptive repair mechanism. We also show that genetic deletion of MET in adult murine acinar cells is linked to increased acinar cell apoptosis, chronic inflammation with fibrosis following alcohol-associated injury. Notably we also found an extensive ductal metaplasia in alcohol-fed mice lacking MET, possibly through the expansion of a stem/ progenitor cell population. Finally, we identified specific alterations of the pancreatic transcriptome mediated by MET signaling during alcohol-associated injury, key for tissue repair and inflammation. Of note, loss of MET signaling results in an up-regulation of CCR2, an important mediator of chronic inflammation. Our preliminary studies support the novel hypothesis that MET signaling promotes acinar regeneration in response to alcohol-associated injury. This hypothesis will be tested in two specific aims. In Aim 1, we will show that MET signaling is indispensable for Acinar-Ductal Metaplasia (ADM), the primary mechanism by which acinar cells restore their numbers following damage. To do this we will use a novel conditional MET knockout mouse specific for adult acinar cells, thereby sparing ductal and progenitor cells, coupled with a ex vivo ADM assay. We will examine the role of MET for specific steps leading to ADM including a) acinar trans differentiation into a ductal-like epithelia and/or b) subsequent redifferentiation of the metaplastic epithelia into functional acina cells. In Aim 2, we will illustrate that loss of MET enhances a CCR2- mediated inflammatory response that exacerbates alcohol-associated injury. Using a targeted pharmacological approach in our MET knockout model of alcohol-associated damage, we will examine the role of CCR2 signaling in acinar injury and whether this signaling may be leveraged to promote acinar renewal. Collectively, the results of our experiments will uncover a novel role for MET in ADM and reducing chronic inflammation, which may result in targeted therapeutics to promote repair of the exocrine pancreas due to alcohol-associated injury.