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The role of CB2 receptors in oxLDL-induced apopotosis and atherogenesis

CB2受体在oxLDL诱导的细胞凋亡和动脉粥样硬化形成中的作用

基本信息

批准号：
7128044
负责人：
DOUGLAS P THEWKE
金额：
$ 21.9万
依托单位：
EAST TENNESSEE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-15 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7128044
关键词：
apoptosis arachidonate atherosclerosis biological signal transduction cannabinoid receptor cytoprotection disease /disorder model genetically modified animals laboratory mouse low density lipoprotein macrophage mitochondria oxidized lipid pathologic process receptor binding receptor expression second messengers

项目摘要

DESCRIPTION (provided by applicant): Our laboratory has been engaged in studies to determine the signal transduction pathway by which naturally occurring oxysterols induce apoptosis in various vascular cells, particularly macrophages. Our published results indicate that arachidonyl esters of these oxysterols are second messengers of the apoptotic response. In an effort to understand the mechanism by which these compounds entrain apoptosis we have begun to examine the hypothesis that arachidonyl oxysterols produce these effects via the cannabinoid 2 (CB2) receptor. Preliminary findings, presented in this proposal, of a loss of the apoptotic response to oxysterol treatment in various cell models defective in CB2 signaling are consistent with this hypothesis. Other studies from our laboratory indicate that one of the physiologically significant consequences of macrophage apoptosis in response to oxysterols is as a protective mechanism against atherosclerosis. This raises the possibility that CB2 signaling of apoptosis in macrophages may serve as one of the signaling pathways of this anti-atherosclerotic effect. To test these ideas regarding the mechanism and physiological significance of arachidonyl oxysterol signaling of apoptosis in macrophages we propose the following specific aims: 1) Determine if arachidonyl oxysterols can induce apoptosis in macrophages. 2) Determine if arachidonyl oxysterols can bind to cannabinoid receptors and modulate their activity. 3) Examine the role of the CB2 receptor in the development of atherosclerosis in mouse models. The results from this investigation may expand our understanding of the link between cannabinoid signaling mechanisms and the mechanisms regulating apoptosis in macrophages. They may also provide new pharmacologically exploitable targets for the development of novel pharmaceuticals for treatment of atherosclerosis.

描述（由申请人提供）：我们的实验室一直在进行研究，以确定天然存在的氧固醇诱导各种血管细胞，特别是巨噬细胞凋亡的信号转导途径。我们发表的研究结果表明，这些氧化固醇的花生四烯酸酯是凋亡反应的第二信使。为了理解这些化合物诱导细胞凋亡的机制，我们已经开始研究花生四烯酸氧化甾醇通过大麻素2（CB 2）受体产生这些作用的假设。初步的调查结果，在这个建议中，在CB2信号传导缺陷的各种细胞模型中对氧固醇治疗的凋亡反应的损失与这一假设一致。我们实验室的其他研究表明，巨噬细胞凋亡对氧化固醇的生理学意义的后果之一是作为一种保护机制，防止动脉粥样硬化。这提高了巨噬细胞中细胞凋亡的CB 2信号传导可能作为这种抗动脉粥样硬化作用的信号传导途径之一的可能性。为了验证这些关于花生四烯酸氧化固醇信号转导在巨噬细胞中的凋亡的机制和生理意义的想法，我们提出了以下具体目标：1）确定花生四烯酸氧化固醇是否可以诱导巨噬细胞中的凋亡。2)确定花生四烯酸氧化固醇是否可以与大麻素受体结合并调节其活性。3)研究CB2受体在小鼠模型动脉粥样硬化发展中的作用。这项研究的结果可能会扩大我们对大麻素信号传导机制和调节巨噬细胞凋亡机制之间联系的理解。它们还可以为开发用于治疗动脉粥样硬化的新药提供新的可开发的靶点。