PPG - Mechanisms of Cardiovascular Protection and Disease

描述(由申请人提供)： 在通过血管紧张素II和高胆固醇血症等应激源促进氧化应激和炎症的途径与通过促进抗氧化和抗炎状态而起保护作用的途径之间存在微妙的平衡。这些通路之间的平衡/失衡影响动脉粥样硬化、高血压、钙化性主动脉瓣狭窄和血栓形成的易感性。该计划的总体主题是定义预防和易患心血管功能障碍和疾病的内源性机制。 该计划中的项目将集中在几个新的假设上。首先，本供资期间的调查结果表明，购买力平价？内皮和血管平滑肌中的依赖通路均可预防动脉粥样硬化的发生。建议进行研究以检验PPAR？并检验PPAR？预防血栓形成和钙化性主动脉瓣狭窄。考虑到关于激活PPAR？的噻唑烷二酮类药物作用的争议，这些研究是及时的和具有临床意义的。第二，肾素-血管紧张素系统是高血压和卒中病理生理学中的关键机制。研究旨在验证肾素-血管紧张素系统导致脑血管功能障碍、钙化性主动脉瓣狭窄和血栓形成的假说。第三，将通过哪些PPAR来研究机制？调节Rho激酶的周转和活性，从而可能导致高血压时血管结构和血管舒缩张力的改变。第四，研究计划验证一个假设，即一种特定的氧化反应，即蛋白蛋氨酸氧化，会损害内皮蛋白血栓调节蛋白的抗凝功能，从而导致动脉粥样硬化的血栓前表型。 该计划的重点和凝聚力都很强。它由四个项目和三个核心组成。研究人员使用复杂的实验方法，包括组织特异性基因改变小鼠，来阐明基本机制。调查人员工作效率高，互动性强，环境也很好。如果该计划的主要目标得以实现，这很可能是基于研究人员的过往记录和协同作用，研究结果将阐明与心血管功能障碍相关的重要机制，并可能转化为动脉粥样硬化和其他心血管疾病的改进治疗。

DESCRIPTION (Provided by Applicant): There is a delicate balance between pathways which promote oxidative stress and inflammation, through stressors such as angiotensin II and hypercholesterolemia, and pathways which are protective by promoting an antioxidant and antiinflammatory state. The balance/imbalance between these pathways influences susceptibility to atherosclerosis, hypertension, calcific aortic valvular stenosis, and thrombosis. The overall theme of this Program is to define endogenous mechanisms that protect against, and predispose to, cardio- vascular dysfunction and disease. The Projects in this Program will focus on several novel hypotheses. First, findings during the current funding period indicate that PPAR? dependent pathways in both endothelium and vascular smooth muscle protect against development of atherosclerosis. Studies are proposed to examine mechanisms of protection by PPAR? and to test the hypothesis that PPAR? protects against thrombosis and calcific aortic valvular stenosis. These studies are timely and clinically relevant considering the controversy about effects of thiazoledinedione drugs, which activate PPAR?. Second, the renin-angiotensin system is a key mechanism in pathophysiology of hypertension and stroke. Studies are proposed to test the hypothesis that the renin- angiotensin system contributes to cerebral vascular dysfunction, calcific aortic valvular stenosis, and thrombosis. Third, mechanisms will be studied by which PPAR? modulates rho kinase turnover and activity, and thus may contribute to altered vascular structure and vasomotor tone in hypertension. Fourth, studies are planned to test the hypothesis that a specific oxidation reaction, protein methionine oxidation, impairs anti-coagulant function of the endothelial protein thrombomodulin, and thereby contributes to the prothrombotic phenotype of atherosclerosis. The Program is tightly focused and cohesive. It consists of four projects and three cores. The investigators use sophisticated experimental approaches, including tissue-specific genetically altered mice, to clarify fundamental mechanisms. The investigators are productive, highly interactive, and the environment is outstanding. If major goals of the Program are accomplished, which is probable based on the track record and synergy of the investigators, the findings will clarify important mechanism related to cardiovascular dysfunction, and may allow translation into improved treatment of atherosclerosis and other cardiovascular diseases.