This application describes a comprehensive research program designed to develop Dr. DeMorrow into an independent research scientist. Through a structured program of seminars, conferences and workshops throughout the duration of the K01 award, she will acquire the necessary background knowledge and analytical skills to achieve this goal. Development of grantsmanship is also emphasized, beginning with applications for intramural funds, graduating to applications for funding from the Veterans Affairs Administration and culminating in an R01 submission to the NIH in the third year of this award. The research plan focuses on the opposing modulatory actions of the endocannabinoids, anadamide and 2-arachidonyl glycerol, on cholangiocarcinoma cell growth. This devastating cancer has very limited treatment options and very poor prognosis, hence the development of novel therapeutic strategies is crucial to improve the clinical outcomes of this disease. Modulation of the endocannabinoid system has been suggested as a potential target for the treatment of a number of cancers. Dr DeMorrow presents novel preliminary evidence indicating that anandamide exerts antiproliferative effects, whereas 2-arachidonyl glycerol has growth promoting effects on cholangiocarcinoma cell growth. These opposing actions appear to be independent of any known cannabinoid receptor and the applicant proposes that it is via the specific interactions and subsequent effects of the endocannabinoids on the lipid raft structures of the plasma membrane. In addition, a differential activation of Notch 1 and Notch 2 by anandamide and 2-arachidonyl glycerol respectively has been observed. Thus, the applicant hypothesizes that the activation of Notch 1 signaling pathways are responsible for AEA-mediated antiproliferative effects, while Notch 2 signaling pathways are responsible for 2-AG growth promoting effects on cholangiocarcinoma cell growth. To address this hypothesis, the applicant proposes 3 sequential specific aims: (1) to further define the differential effects of endocannabinoids on cholangiocarcinoma growth via cannabinoid receptor-independent, lipid raft mediated pathways;(2) to demonstrate that the differential regulation of cholangiocarcinoma growth by endocannabinoids requires Notch signal transduction pathways, and (3) to show that the differential activation of the Notch signaling pathways by endocannabinoids is dependent upon lipid rafts.
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