The Hippo signaling pathway in pancreatic epithelial cells orchestrate the inflammatory response R01

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Project Summary The inflammatory disorders of the pancreas have two forms, acute and chronic. Acute pancreatitis causes severe illness and reduces life expectancy. However, besides supportive care, there is no effective treatment for the disease due to a lack of understanding of the early cellular events important in the pathophysiology of this disease. Not only is chronic pancreatitis as bad in that it does not heal or improve and only gets worse over time leading to permanent damage of the pancreas, it is also the top risk factor for pancreatic adenocarcinoma (PDAC). Similar to the acute form, there is no effective treatment for this disease. This tissue damage causes a rapid sterile inflammatory response (SIR) characterized by edema, immune cell infiltration, and further acinar cell death. A lot of evidence points towards the SIR having a vital role in pancreatic damage, but the crucial link between acinar cell injury and initiation of the SIR has not been well understood. The Hippo signaling pathway is best known for its ability in controlling organ size, cell proliferation and regeneration. Noticeably, this pathway responds to various upstream stimuli such as mechanical signals, cellular stress, extracellular stimuli and adhesion cues, making it a good candidate as a microenvironment sensor for epithelial cells to orchestrate the inflammatory response during tissue injury and repair. Nevertheless, the role of the Hippo pathway in directly regulating inflammatory reactions has not been investigated. Our preliminary data showed that inactivation of the Hippo pathway by knocking out Lats1&2, specifically in acinar cells, rapidly induced the inflammatory response in the pancreas. Notably, our unpublished data indicated that this inflammatory response was not the secondary effect caused by the death of Lats1&2 deficient acinar cells, suggesting the novel function of the Hippo pathway to directly regulate epithelial-immune cell interactions. We hypothesize that YAP/TAZ mediated transcription in Hippo pathway- inactivated pancreatic acinar cells plays important roles in recruiting and educating immune cells to orchestrate the inflammatory response. Our hypothesis will be tested with three specific aims. First, we will test the hypothesis that expression of YAP1 or TAZ are necessary for induction of pro-inflammatory genes in Lats1&2 null pancreatic acinar cells using a genetic approach. Second, we will investigate how YAP and TAZ induce inflammation through transcriptional regulation. Third, we will test the hypothesis that Yap and/or Taz are necessary for the inflammation and fibrosis associated with acute or chronic pancreatitis. Our proposal will not only investigate the novel functions of Hippo pathways, but will also address the fundamental mechanisms by which epithelial cells specify the communication with immune cells during inflammation. Our research will have important implications to improve understanding of the pathophysiology of inflammatory diseases in the pancreas and for potential therapeutic development.