GPCR Signaling and Vascular Wall Remodeling

GPCR 信号传导和血管壁重塑

基本信息

批准号：
9312305
负责人：
GADIPARTHI N RAO
金额：
$ 47.59万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9312305
关键词：
ARHGEF1 gene ATF2 gene ATP binding cassette transporter 1 ATP-Binding Cassette Transporters Address Apolipoprotein E Applications Grants Arterial Fatty Streak Atherosclerosis Attenuated Blood Platelets Blood Vessels Blood coagulation CD36 gene Cause of Death Chemotactic Factors Cholesterol Chronic Disease Clustered Regularly Interspaced Short Palindromic Repeats Complex Data Dissociation Dominant-Negative Mutation Dose EMSA Endothelial Cells Environmental Risk Factor Event Fibroblasts Foam Cells Functional disorder Funding G Protein-Coupled Receptor Signaling GAB1 gene Genetic Risk Inflammation Knowledge Lesion Link Luciferases Mediating Messenger RNA Mitogens Mus Muscle Cells Myocardial Infarction PAR-1 Receptor Pathogenesis Peritoneal Macrophages Pharmacology Play Proteinase-Activated Receptors Proteins PubMed Regulatory Element Reporting Role Serine Protease Signal Transduction Site-Directed Mutagenesis Small Interfering RNA Smooth Muscle Myocytes Societies Stroke Testing Thrombin Thrombosis Thrombus Time Study Ubiquitination Vascular Diseases Vascular Smooth Muscle atherogenesis atherothrombosis base cell type cholesterol transporters chromatin immunoprecipitation cullin-3 experimental study feeding insight macrophage migration monocyte mortality novel overexpression oxidized lipid oxidized low density lipoprotein promoter receptor response scaffold scavenger receptor translational impact ubiquitin-protein ligase uptake western diet

项目摘要

Atherosclerosis is a chronic disease of arterial wall caused by various genetic and environmental risk factors and is the foremost cause of mortality worldwide. Inflammation plays a critical role in atherogenesis. Protease- activated receptor 1 (Par1) that mediates the cellular effects of thrombin, a serine protease, has been reported to play an important role in inflammation. In addition, a large body of data suggests that Par1 plays an essential role in atherothrombosis. Despite the role of Par1 in inflammation and atherothrombosis and the fact that increased expression of Par1 is observed in atherosclerotic plaques, nothing is known about its role in atherogenesis. In this context, we recently discovered that thrombin induces the expression of CD36, a scavenger receptor linked to oxLDL uptake and foam cell formation, and this event requires Gα12/13, Pyk2, Gab1, PKCθ and ATF2 activation downstream to Par1. In addition, we found that thrombin induces the depletion of ABCA1, a reverse cholesterol transporter and attenuates cholesterol efflux. Interestingly, ABCA1 was found to exist in complex with GSK3β and, upon treatment with thrombin, it dissociates from GSK3β, associates with cullin 3, a component of E3 ligases, and undergoes degradation. Based on these novel observations, we hypothesize that thrombin-Par1 axis plays a major role in atherogenesis. To test this central hypothesis, we propose to address the following three specific aims: Specific Aim 1: Par1 plays a central role in atherogenesis. Specific Aim 2: PKCθ via activating ATF2 and enhancing CD36 expression, oxLDL uptake and foam cell formation plays a crucial role in atherogenesis. Specific Aim 3: Overexpression of GSK3β stabilizes ABCA1, enhances cholesterol efflux and protects from atherogenesis. The results of the proposed studies will provide new mechanistic insights into the pathophysiology of atherosclerosis and explore the translational impact of thrombin-Par1 signaling in this debilitating vascular disease.

动脉粥样硬化是由多种遗传和环境危险因素引起的动脉壁慢性疾病炎症是导致动脉粥样硬化的主要原因。据报道，激活的受体 1 (Par1) 介导凝血酶（一种丝氨酸蛋白酶）的细胞作用此外，大量数据表明 Par1 在炎症中发挥着重要作用。尽管 Par1 在炎症和动脉粥样硬化血栓形成中发挥着重要作用。尽管在动脉粥样硬化斑块中观察到 Par1 表达增加，但对其在动脉粥样硬化斑块中的作用尚不清楚。在这种情况下，我们最近发现凝血酶诱导 CD36 的表达，CD36 是一种清道夫受体与 oxLDL 摄取和泡沫细胞形成相关，该事件需要 Gα12/13、Pyk2、 Par1 下游的 Gab1、PKCθ 和 ATF2 激活此外，我们发现凝血酶诱导 ABCA1（一种反向胆固醇转运蛋白）的消耗并减弱胆固醇流出。被发现与 GSK3β 形成复合物，并且在用凝血酶处理后，它与 GSK3β 解离，与 E3 连接酶的一个组成部分 cullin 3 结合，并根据这些小说进行降解。根据观察，我们认为凝血酶-Par1 轴在动脉粥样硬化形成中起主要作用，以测试这一中枢。假设，我们建议解决以下三个具体目标：具体目标 1：Par1 发挥核心作用具体目标 2：PKCθ 通过激活 ATF2 和增强 CD36 表达、oxLDL 摄取泡沫细胞的形成在动脉粥样硬化形成中起着至关重要的作用。具体目标 3：GSK3β 的过度表达。稳定 ABCA1，增强胆固醇流出并防止动脉粥样硬化。研究将为动脉粥样硬化的病理生理学提供新的机制见解并探索凝血酶-Par1 信号转导在这种使人衰弱的血管疾病中的翻译影响。