PPG - Oxidative Mechanisms in Vascular Disease

描述（由申请人提供）： 内皮功能异常在多种血管疾病的病理生理学中起着关键作用。该计划的总体主题是动脉粥样硬化和高血压中内皮功能障碍的机制，重点是氧化和抗氧化机制之间的平衡，以及炎症和抗炎机制之间的平衡。在这些令人兴奋的研究领域转化为动脉粥样硬化和其他血管疾病的有效治疗之前，需要更好地了解氧化损伤和炎症。研究提出了几个新的假设。这些目标是重点突出和有凝聚力的。首先，血管紧张素II可能会导致高血压，在很大程度上通过氧化和炎症机制。其次，白细胞介素-10是一种重要的抗炎细胞因子，可以预防血管疾病，包括高血压。第三，先天性免疫应答可由非巨噬细胞血管细胞产生，并且对几种炎症介质产生免疫应答。第四，抗氧化机制的损害，包括细胞外和锰超氧化物歧化酶，可能是非常重要的血管疾病。第五，动脉粥样硬化小鼠的加速血栓形成是由血栓调节蛋白的氧化失活和抗凝蛋白C的活化降低引起的。第六，过氧化物酶体增殖物激活受体γ可以通过激活和抑制血管壁中的靶基因来调节血管功能和动脉粥样硬化形成。该计划包括四个项目和一个管理核心，其中包括一个生物信息学部分。研究人员在每个项目中整合了药理学方法，最先进的分子方法，小鼠中复杂的生理测量和新型遗传改变小鼠。调查员在一个出色的环境中密切合作，一直保持着出色的工作效率。该计划的长期目标是有助于更好地了解血管疾病的氧化和炎症机制，从而改善动脉粥样硬化和其他血管疾病的治疗。

DESCRIPTION (provided by applicant): Abnormal endothelial function plays a key role in the pathophysiology of several vascular diseases. The overall theme of this Program is mechanisms of endothelial dysfunction in atherosclerosis and hypertension, with emphasis on the balance between oxidative and antioxidant mechanisms, and between inflammation and anti-inflammatory mechanisms. Better understanding of oxidative injury and inflammation will be needed before these exciting areas of research can be translated into effective treatment for atherosclerosis and other vascular diseases. Studies are proposed to examine several novel hypotheses. The goals are tightly focused and cohesive. First, angiotensin II may contribute to hypertension, in substantial part by oxidative and inflammatory mechanisms. Second, interleukin-10 is an important anti-inflammatory cytokine which may protect against vascular disease, including hypertension. Third, an innate immune response may be generated by non-macrophage vascular cells, and transduce immune responses to several inflammatory mediators. Fourth, impairment of antioxidant mechanisms, including extracellular and manganese superoxide dismutases, may be of great importance in vascular disease. Fifth, accelerated thrombosis in atherosclerotic mice is produced by oxidative inactivation of thrombomodulin and decreased activation of the anticoagulant protein C. Sixth, peroxisome proliferator activated receptor gamma may modulate vascular function and atherogenesis through activation and repression of target genes in the blood vessel wall. The Program consists of four projects and an administration core, which includes a bioinformatics section. The investigators integrate pharmacological approaches, state-of-the-art molecular approaches, sophisticated physiological measurements in mice, and novel genetically altered mice in each project. There is a sustained record of excellent productivity, with close collaboration among the investigators within an outstanding environment. The long-term goal of the Program is to contribute to better understanding of oxidative and inflammatory mechanisms of vascular diseases, to allow translation into improved treatment of atherosclerosis and other vascular diseases.