Endocannabinoid Regulation of Cholangiocarcinoma Cell Growth

描述(由申请人提供)： 这份申请描述了一个全面的研究计划，旨在将德莫罗博士培养成一名独立的研究科学家。通过在K01奖项期间组织的研讨会、会议和研讨会，她将获得必要的背景知识和分析技能，以实现这一目标。还强调了资助人精神的发展，从申请内部资金开始，逐步到退伍军人事务管理局的资金申请，最后在该奖项的第三年向国家卫生研究院提交了R01。该研究计划的重点是内源性大麻素对胆管癌细胞生长的相反调节作用，即内源性大麻酰胺和2-花生四烯基甘油。这种毁灭性的癌症的治疗选择非常有限，预后非常差，因此开发新的治疗策略对于改善这种疾病的临床结果至关重要。内源性大麻素系统的调节已被认为是治疗一些癌症的潜在靶点。德莫罗博士提出了新的初步证据，表明anandide具有抑制增殖的作用，而2-花生四烯基甘油对胆管癌细胞的生长具有促进作用。这些相反的作用似乎独立于任何已知的大麻素受体，申请人提出，它是通过内源性大麻素对质膜脂筏结构的特定相互作用和随后的影响而产生的。此外，还观察到Anandamide和2-花生四烯基甘油对Notch 1和Notch 2的不同激活作用。因此，申请人假设Notch 1信号通路的激活负责AEA介导的抗增殖作用，而Notch 2信号通路负责2-AG对胆管癌细胞生长的促进作用。为了解决这一假设，申请人提出了三个连续的特定目标：(1)通过大麻素受体非依赖的脂筏介导的途径，进一步确定内源性大麻素对胆管癌细胞生长的不同影响；(2)证明内源性大麻素对胆管癌细胞生长的差异性调控需要Notch信号转导通路；(3)证明内源性大麻素对Notch信号通路的差异性激活依赖于脂筏。

DESCRIPTION (provided by applicant): 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 [sic] 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.