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Investigating how p110α PI3K and ADAM10 contribute to pancreatic disease

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dc.contributor.advisor Crawford, Howard C en_US
dc.contributor.author Hall, Jason C. en_US
dc.contributor.other Department of Molecular and Cellular Pharmacology. en_US
dc.date.accessioned 2017-09-20T16:50:32Z
dc.date.available 2017-09-20T16:50:32Z
dc.date.issued 2015-08-01 en_US
dc.identifier.uri http://hdl.handle.net/11401/76519 en_US
dc.description 117 pg. en_US
dc.description.abstract Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related deaths in the United States, with a 6% 5-year survival rate. Chronic pancreatitis (CP) is a debilitating disease that raises your risk for developing PDAC 13 fold. Since current therapies are not improving patient outcome, understanding the molecular mechanisms behind the formation and progression of these diseases are imperative for finding new molecularly targeted therapy. Kras is the earliest and most commonly mutated oncogene in PDAC. Pancreatic mouse models expressing oncogenic Kras spontaneously form pancreatic tumors. Since targeting Kras directly has been unsuccessful many have tried inhibiting other molecules in the cell-signaling pathway to block tumor formation. Previously, we have discovered that blocking molecules in the epidermal growth factor receptor (EGFR) pathway inhibits Kras activity and prevents tumor formation at an early stage of epithelial change. Acinar to ductal metaplasia (ADM) is an event commonly seen in CP, where acinar cells change structure to express a ductal phenotype. Normally, ADM in CP progresses no further, but it is hypothesized that these metaplastic cells can become tumors if they express mutant Kras. My first study examines the catalytic subunit of phosphoinositide 3-kinase (PI3K), p110α , an enzyme that associates with Kras and is activated by receptor tyrosine kinases, such as EGFR. Here I show that knocking out or pharmacologically inhibiting p110α in mice prevents the development of CP. ADM and subsequent inflammatory responses in this disease does not occur when these mice are subjected to experimental pancreatitis. The actin-cytoskeleton rearrangement necessary for ADM is also blocked when p110α is ablated or inhibited, suggesting that p110α may have a role in actin remodeling. Secondly, I investigated A disintegrin and metalloproteinase (ADAM10), a protease known for causing the activation of Notch, whose signaling pathway has been shown to be downstream of EGFR. By ablating ADAM10 in a PDAC mouse model, we show tumor progression is altered leading to the development of large cystic lesions, decreased metastasis and a longer lifespan. In summary, my work demonstrates that p110α and ADAM10 may independently alter the course of pancreatic disease and may potentially be therapeutic targets. en_US
dc.description.sponsorship This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. en_US
dc.format Monograph en_US
dc.format.medium Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Cellular biology en_US
dc.subject.other acinar to ductal metaplasia (ADM), ADAM 10, Kras, Pancreatitis, PI3K, Rac en_US
dc.title Investigating how p110α PI3K and ADAM10 contribute to pancreatic disease en_US
dc.type Dissertation en_US
dc.mimetype Application/PDF en_US
dc.contributor.committeemember Frohman, Michael en_US
dc.contributor.committeemember Lin, Richard en_US
dc.contributor.committeemember Li, Feng-Qian en_US
dc.contributor.committeemember Ma, Yupo. en_US

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