G PROTEIN SIGNALING--ATHEROGENIC MECHANISMS OF INHIBITIO

G蛋白信号传导--致动脉粥样硬化的抑制机制

• 批准号: 6389264
• 负责人: DAVID P HAJJAR
• 金额: $ 56.55万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6389264
• 关键词: G protein; atherosclerosis; biological signal transduction; blood lipoprotein metabolism; caveolas; cholesterol; eicosanoid metabolism; gel mobility shift assay; gene expression; human tissue; laboratory rabbit; laboratory rat; lipid metabolism; macrophage; membrane lipids; mitogen activated protein kinase; molecular weight; muscle cells; phospholipids; prostacyclins; prostaglandin endoperoxide synthase; protein kinase C; transcription factor; vascular endothelium; vascular smooth muscle

Accumulation of cholesteryl ester and other lipids with macrophages, vascular smooth muscle cells (SMC) and the extracellular matrix is an early and persistent hallmark of the atherosclerotic lesion. Lipid accumulation is associated with the impairment of vascular relaxation mediated by prostacyclin (PGI2). We have demonstrated that cholesteryl ester-enrichment of arterial SMC, as occurs in atherosclerosis, alters eicosanoid production. The overall goal of this renewal application is to continue our studies to define the mechanisms by which foam cell development inhibits signaling pathways responsible for the generation of PGI2. In this revised proposal, we will advance our hypothesis that G-protein-mediated signaling processes involving cylooxygenase gene expression are altered in SMC-derived foam cells. The broad goal of this proposal is to define the relationship between low molecular weight and heterotrimeric G-protein assembly in arterial SMC, and to determine the impact of cholesterol-enrichment on this process. Experiments proposed in Aim 1 will test the hypothesis that cholesterol enrichment of SMC alters heterotrimeric G-protein content, assembly on cell membranes, and signaling. In Aim 2, we will evaluate the mechanisms by which cell membrane cholesterol content alters electrostatic interactions between isoprenylated G-proteins, phospholipids and caveolae-associated signaling molecules resulting in the inhibition of G-proteins, phospholipids and caveolae-associated signaling molecules resulting in the inhibition of G-protein function. Finally, in Aim 3, we will assess the role of cholesterol-enrichment and oxygenated sterols on the inhibition of transcriptional and post-transcriptional regulation of cyclooxygenase-2 (COX-2). We believe that this revised proposal represents an integrated and focused approach to understanding the role of G-protein mediated signaling events in the regulation of eicosanoid synthesis in SMC and in the alterations that occur in the signaling pathways during atherosclerotic foam cell development.

胆固醇酯和其他具有巨噬细胞，血管平滑肌细胞（SMC）和细胞外基质的脂质的积累是动脉粥样硬化病变的早期和持久标志。脂质积累与前列环蛋白（PGI2）介导的血管松弛损伤有关。我们已经证明，动脉粥样硬化中的动脉SMC的胆固醇酯富集会改变类花生酸的产生。这种更新应用的总体目标是继续我们的研究来定义泡沫细胞发育抑制负责PGI2产生的信号传导途径的机制。在这项修订后的建议中，我们将推进我们的假设，即涉及Cy氧酶基因表达的G蛋白介导的信号传导过程在SMC衍生的泡沫细胞中会改变。该提案的广泛目标是定义动脉SMC中低分子量与异源三聚体G蛋白组装之间的关系，并确定胆固醇 - 富集在此过程中的影响。 AIM 1中提出的实验将检验以下假设：SMC的胆固醇富集会改变异源三聚体G蛋白含量，细胞膜上的组装和信号传导。在AIM 2中，我们将评估细胞膜胆固醇含量改变异源肾上腺素化的G蛋白之间的静电相互作用，与Caveolae相关的信号分子分子导致G-蛋白，磷脂磷脂，磷酸磷脂和洞穴相关的信号分子的抑制作用。最后，在AIM 3中，我们将评估胆固醇 - 富集和氧固醇对抑制转录和转录后调节环氧合酶2（COX-2）的作用。我们认为，这项修订后的建议代表了一种综合和集中的方法，用于理解G蛋白介导的信号传导事件在SMC中eicosanoid合成的调节以及动脉粥样硬化泡沫细胞发育过程中信号传导途径中发生的变化中的作用。