DESCRIPTION (provided by applicant): Acute Pancreatitis (AP) is potentially lethal when severe and is increasing in incidence, resulting in significant health care burden and costs. Currently AP has no specific therapy apart from supportive care. The conventional strategy of targeting a single mechanistically important step has unfortunately not been successful on the clinical front, likely due to the multiple deleterious signaling pathways simultaneously activated in AP. Additionally, modifiers like obesity worsen outcomes from an initiator which may otherwise cause mild AP, adding an additional layer of complexity. We thus aimed at identifying a target that would be involved in multiple mechanisms of AP initiation and its lipotoxic exacerbation during obesity. Based on its multiple roles, we identified c-Src as such a target, which also is pharmacologically relevant to human disease. PRELIMINARY DATA: We found evidence of c-Src's involvement at numerous levels during AP initiation. These included c-Src dependent antegrade extension of the Golgi, trafficking of chymotrypsin through the Golgi, trypsinogen activation, F-actin remodeling, basolateral release of pancreatic enzymes and acinar cell death. Strong evidence implicates unsaturated fatty acids (UFA) in the lipotoxic exacerbation of AP during obesity. We found proof of c-Src's involvement in this lipotoxic exacerbation. This included increased expression of c-Src in fat necrosis, associated with increased pancreatic lipase amounts in adipose tissue, along with a reduction in lipolysis, lipotoxic acinar injury, and improvement in severe AP by inhibitors of c-Src. This is further supported by c-Src expression causing a loss of lipid droplets, along with increasing lipase amounts in 3T3LI cells, and Src activation being noted in human fat necrosis and in response to linoleic acid (LA). We therefore hypothesize that c-Src is a therapeutic target in AP since it is involved in multiple steps during AP initiation and its lipotoxic exacerbation. PROPOSAL: We propose to study the multiple roles of c-Src in the initiation and lipotoxic exacerbation of AP. These include its role in regulating trafficking of cargo through the Golgi, trypsinogen activation basolateral leakage and acinar cell death. Based on preliminary data showing its multiple roles in lipotoxic exacerbation of AP, we also plan to explore the role of c-Src in lipotoxic mediator (e.g. UFA), generation and how c-Src further regulates the acinar and inflammatory response to these lipotoxic mediators. This includes c-Src's role in acinar and inflammatory cell death, and in the generation of inflammatory mediators by acinar cells, adipocytes. Lastly, we will study whether genetic or pharmacologic inhibition of c-Src improves outcomes in both mild and obesity associated lethal AP. These novel studies could open a new multimodal therapeutic frontier for AP by defining the role of a single pharmacologically amenable therapeutic target, i.e. c-Src (for which there are drugs currently approved for human use) in multiple distinct steps during the initiation and lipotoxic exacerbation of AP.
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