Endocannabinoid Regulation of Cholangiocarcinoma Cell Growth

这份申请描述了一个全面的研究计划，旨在将德莫罗博士发展成一名 独立研究科学家。通过有组织的研讨会、会议和讲习班计划 在K01奖项的整个有效期内，她将获得必要的背景知识和 达到这一目标的分析技能。还强调了对风度的发展，从 申请校内经费，毕业申请退伍军人事务部的经费 并最终在该奖项的第三年向美国国立卫生研究院提交了R01。这项研究 PLAN侧重于内源性大麻素、阿那达胺和2-花生四烯基的相反调节作用 甘油对胆管癌细胞生长的影响。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改善临床至关重要。 这种疾病的后果。内源性大麻素系统的调节被认为是一种潜在的 治疗多种癌症的靶点。德莫罗博士提出了新的初步证据表明 烷胺具有抗增殖作用，而2-花生四烯基甘油具有促生长作用。 对胆管癌细胞生长的影响。这些对立的行为似乎独立于任何已知的 和申请人提出，它是通过特定的相互作用和随后的 内源性大麻素对质膜脂筏结构的影响。此外，a 双胺和2-花生四烯基甘油对Notch 1和Notch 2的不同激活作用 被观察到了。因此，申请人假设Notch 1信号通路的激活是 负责AEA介导的抗增殖作用，而Notch 2信号通路负责 2-AG对胆管癌细胞的生长促进作用。为了解决这一假设，申请人 提出了三个连续的具体目标：(1)进一步确定内源性大麻素对 胆管癌细胞通过大麻素受体非依赖性、脂筏介导的途径生长；(2) 证明内源性大麻素对胆管癌细胞生长的不同调控需要 Notch信号转导途径，以及(3)显示Notch信号的差异激活 内源性大麻素途径依赖于脂筏。

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.