Pancreatitis, an acute or chronic inflammatory disease of the pancreas, results in significant morbidity and mortality in the United States and within our US veteran population. Trends over the past few decades show an increased incidence of pancreatitis in the US population. The majority of acute pancreatitis cases are related to alcohol or gallstones. Chronic pancreatitis, which results in progressive fibrosis and loss of parenchyma, is generally secondary to recurrent episodes of acute inflammation with alcohol abuse being a major precipitating factor. Extensive efforts have been dedicated to understanding the causes and mechanisms of pancreatic injury;however, there is very limited knowledge pertaining to the role of genetics in modifying the susceptibility and progression of acute and chronic pancreatitis. A genetic predisposition to alcohol-induced pancreatitis is suggested by its higher prevalence in males as well as in African Americans. A clear understanding of the pathogenesis of alcoholic pancreatitis has been hindered by the limited availability of experimental models. However, several mouse pancreatitis models are available, with the most studied being cerulein administration which can cause acute and chronic pancreatitis and has a synergistic effect if given with ethanol. Our hypothesis is that genetic modifiers can be identified that promote or ameliorate the extent of pancreatitis, and such modifiers serve as potential therapeutic targets. This hypothesis, which is supported by significant preliminary results and publication record, will be tested by: (i) Identifying mouse strains that are susceptible or resistant to acute and chronic experimental pancreatitis (Aims 1 and 2);(ii) Utilizing the mouse strains from Aims 1 and 2, together with proteomic and genomic approaches, to identify molecular pathways that associate with susceptibility or resistance to experimental pancreatitis (Aim 3);and (iii) Testing the effect of targeting the coagulation pathway, via heparin, as a therapeutic modality in experimental pancreatitis (Aim 4). Completion of our aims should markedly improve our limited knowledge regarding genetic modifiers of experimental pancreatitis and provide insights regarding the utility of the coagulation pathway as a treatment target. Findings in the experimental models can then be tested in human pancreatitis, and may lead to potential novel therapeutic approaches.
The overarching goal of this proposal is to identify genetic influences on the predisposition to acute and chronic pancreatitis using mice as a model system. Understanding the role of genetic factors is highly beneficial and relevant since it provides potential therapeutic targets that are sorely lacking in human pancreatitis, and provides possible molecular explanations to the observed differences in susceptibility to pancreatitis in humans.
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