| dc.identifier.uri | http://hdl.handle.net/11401/77108 | |
| 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 | |
| dc.format.medium | Electronic Resource | en_US |
| dc.language.iso | en_US | |
| dc.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dc.type | Dissertation | |
| dcterms.abstract | Pancreatic cancer is the fourth leading cause of cancer related death in the United States with most patients succumbing to the disease within a year of diagnosis. Kras mutations are present in the vast majority of pancreatic cancers, though the full mechanism behind Kras induced tumorigenesis is not well defined. Both the EGFR and Notch signaling pathways have been implicated in the formation of precursor lesions from normal acinar cells in a process known as acinar to ductal metaplasia (ADM). Inhibition of MEK kinase downstream of either EGFR or mutant Kras has been shown to be required for ADM formation and subsequent tumorigenesis in a mouse model of pancreatic cancer. However, pharmacological inhibition of MEK prevents the interrogation of individual MEK isoforms, MEK1 and MEK2. In this study, I describe the generation of two novel mouse models using RNA interference to selectively knockdown MEK1, MEK2, or a combination of both. I then investigated the contributions of MEK kinases in pancreatitis, an inflammatory disease which is a risk factor for pancreatic cancer, and Kras initiated tumorigenesis. I have found that combined knockdown of both MEK1 and MEK2, but not knockdown of either alone, confer protection against chronic pancreatitis, and a partial protection against Kras driven tumorigenesis. I next investigated the roles of EGFR and Notch in ADM using primary acinar explants in an ex vivo transdifferentiation assay, as Notch has been described as a downstream target of EGFR and Ras signaling. Notch induced ADM was blocked by genetic ablation of EGFR in acinar cells, which could be rescued by the expression of oncogenic Kras. Additionally inhibition of MEK kinase was able to block Notch induced ADM in WT acinar cells, and well as the acinar cells lacking EGFR and expressing oncogenic Kras. I further investigated the connection of EGFR and Notch pathway components and found a requirement for MEK signaling in both Notch and Kras driven ADM. Taken together, these results demonstrate a central role of MEK kinase in driving the process of ADM and subsequent development of pancreatic cancer. | |
| dcterms.available | 2017-09-20T16:51:59Z | |
| dcterms.contributor | Crawford, Howard C | en_US |
| dcterms.contributor | Sampson, Nicole | en_US |
| dcterms.contributor | Zong, Wei-Xing. | en_US |
| dcterms.contributor | Carrico, Isaac S | en_US |
| dcterms.creator | Halbrook, Christopher James | |
| dcterms.dateAccepted | 2017-09-20T16:51:59Z | |
| dcterms.dateSubmitted | 2017-09-20T16:51:59Z | |
| dcterms.description | Department of Chemistry. | en_US |
| dcterms.extent | 184 pg. | en_US |
| dcterms.format | Application/PDF | en_US |
| dcterms.format | Monograph | |
| dcterms.identifier | http://hdl.handle.net/11401/77108 | |
| dcterms.issued | 2015-12-01 | |
| dcterms.language | en_US | |
| dcterms.provenance | Made available in DSpace on 2017-09-20T16:51:59Z (GMT). No. of bitstreams: 1
Halbrook_grad.sunysb_0771E_12291.pdf: 21027772 bytes, checksum: c1a22fe17a7e4fa016bbc6888a38729a (MD5)
Previous issue date: 1 | en |
| dcterms.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dcterms.subject | Chemistry | |
| dcterms.subject | ADM, EGFR, Kras, MEK, Notch, PDAC | |
| dcterms.title | Developmental and Receptor-Mediated Pathways Define Acinar Cell Plasticity | |
| dcterms.type | Dissertation | |
