Endocannabinoid Regulation of Cholangiocarcinoma Cell Growth

内源性大麻素对胆管癌细胞生长的调节

• 批准号: 7879813
• 负责人: Sharon DeMorrow
• 金额: $ 5.4万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-10 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7879813
• 关键词: 2-arachidonylglycerol; Address; Award; Cell membrane; Cholangiocarcinoma; Clinical; Data; Development; Disease Outcome; Educational workshop; Endocannabinoids; Funding; Goals; Growth; Knowledge; Malignant Neoplasms; Mediating; Membrane Microdomains; Mentored Research Scientist Development Award; Notch Signaling Pathway; Pathway interactions; Regulation; Research; Scientist; Signal Pathway; Signal Transduction Pathway; Structure; System; Testing; United States National Institutes of Health; Veterans; anandamide; base; cannabinoid receptor; cell growth; design; improved; notch protein; novel; novel therapeutics; outcome forecast; programs; research study; skills; symposium; treatment strategy

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.

该申请描述了一项综合研究计划，旨在将 DeMorrow 博士培养成一名 独立研究科学家。通过研讨会、会议和讲习班的结构化计划 在 K01 奖期间，她将获得必要的背景知识和 分析能力来实现这一目标。还强调了赠款精神的发展，首先是 申请校内资金，逐渐申请退伍军人事务部的资金 管理并最终在该奖项的第三年向 NIH 提交了 R01。研究 计划重点关注内源性大麻素、anadamide 和 2-arachidonyl 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， 预后极差，因此开发新的治疗策略对于改善临床表现至关重要 这种疾病的结果。内源性大麻素系统的调节被认为是一种潜在的 治疗多种癌症的目标。德莫罗博士提出了新的初步证据表明 anandamide 具有抗增殖作用，而 2-花生四烯酸甘油具有促进生长作用 对胆管癌细胞生长的影响。这些相反的行动似乎独立于任何已知的 大麻素受体和申请人提出，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，一个 Anandamide 和 2-花生四烯酸甘油分别对 Notch 1 和 Notch 2 的差异激活具有 被观察到。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 信号通路则负责 2-AG 对胆管癌细胞生长的促进作用。为了解决这个假设，申请人 提出了 3 个连续的具体目标：(1) 进一步定义内源性大麻素对 胆管癌通过不依赖大麻素受体的脂筏介导途径生长； (2) 至 证明内源性大麻素对胆管癌生长的差异调节需要 Notch 信号转导途径，以及 (3) 表明 Notch 信号传导的差异激活 内源性大麻素的途径依赖于脂筏。