Vascular Inflammation and Atherosclerosis

描述(由申请人提供)： 有证据表明，炎症在临床上显著的动脉粥样硬化的发展过程中的每个阶段都有作用。重要的是，循环炎症标志物水平升高的患者，如C-反应蛋白和ICAM-1，心血管事件的风险增加。对于越来越多的2型糖尿病患者和代谢综合征患者来说，情况尤其如此。PPG方案的主要假设是，内皮细胞和血管平滑肌细胞中的特定促炎事件调节动脉粥样硬化的严重程度。我们的方法是识别和表征促进血管炎症的信号转导机制。我们正在使用转录、转录后和翻译后修饰调节的联合分析。候选信号通路包括硫氧还蛋白、PPAR-γ、MCP-1和环核苷酸磷酸二酯酶的流动调节。我们的目标是证明这些候选机制调节低密度脂蛋白受体缺陷小鼠动脉粥样硬化的发展和进展。我们相信，PPG机制将通过营造一个充满活力和高度集中的环境来促进这些目标，这将促进我们对血管中信号转导机制的理解。此外，通过创建组织病理学和成像核心，分析转基因和基因敲除小鼠模型所需的专业知识将随时可用。我们预计，本提案中研究人员之间的互动将为炎症在动脉粥样硬化中的致病作用提供新的见解。

DESCRIPTION (provided by applicant): There is evidence that inflammation contributes at each stage in the development of clinically significant Atherosclerosis. Importantly, patients with elevated levels of circulating inflammatory markers such as C-reactive protein and ICAM-1 are at increased risk of cardiovascular events. This is especially true for the growing numbers of Type 2 diabetics and patients with the metabolic syndrome. The major hypothesis of this PPG proposal is that specific pro-inflammatory events in endothelial cells and vascular smooth muscle cells modulate the severity of atherosclerosis. Our approach is to identify and characterize signal transduction mechanisms that promote vascular inflammation. We are using combined analyses of regulation by transcription, post-transcriptional, and post-translational modifications. The candidate signal pathways include flow-mediated regulation of thioredoxin, PPAR-gamma, MCP-1, and cyclic nucleotide phosphodiesterases. Our goals are to prove that these candidate mechanisms modulate the development and progression of atherosclerosis in the LDL receptor deficient mouse. We believe that the PPG mechanism will facilitate these goals by fostering a vibrant and highly focused environment that will advance our understanding of signal transduction mechanisms in blood vessels. In addition, by creating histopathology and imaging cores the expertise necessary for the analysis of transgenic and knockout mouse models will be readily available. We anticipate that the interactions among investigators in the present proposal will provide new insights into the pathogenic roles of inflammation in atherosclerosis.