PPG - Mechanisms of Cardiovascular Protection and Disease

描述（申请人提供）： 在促进氧化应激和炎症的途径之间存在微妙的平衡，通过应激源如血管紧张素II和高胆固醇血症，以及通过促进抗氧化剂和维生素C状态来保护的途径。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保护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。首先，在目前的资助期间的调查结果表明，PPAR？内皮和血管平滑肌中的依赖性途径防止动脉粥样硬化的发展。研究提出审查机制的保护，通过过氧化物酶体增殖物激活受体？为了验证这个假设，防止血栓形成和钙化性主动脉瓣狭窄。考虑到噻唑烷二酮类药物（可激活PPAR？）的作用存在争议，这些研究具有及时性和临床相关性。第二，肾素-血管紧张素系统是高血压和中风的病理生理学中的关键机制。提出了研究来验证假设，即肾素-血管紧张素系统有助于脑血管功能障碍，钙化性主动脉瓣狭窄和血栓形成。第三，机制将研究通过哪些PPAR？调节rho激酶的周转和活性，因此可能有助于改变高血压的血管结构和血管紧张度。第四，研究计划测试的假设，一个特定的氧化反应，蛋白质蛋氨酸氧化，损害抗凝功能的内皮蛋白血栓调节蛋白，从而有助于动脉粥样硬化的血栓形成前表型。 该方案重点突出，具有凝聚力。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，包括组织特异性遗传改变小鼠，以阐明基本机制。调查人员富有成效，高度互动，环境也很出色。如果该计划的主要目标得以实现，这可能是基于跟踪记录和研究人员的协同作用，这些发现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善治疗。

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.