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。该计划的总主题是动脉粥样硬化和高血压的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。在将这些激动人心的研究领域转化为对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。建议进行研究，以检验几个新的假设。这些目标高度集中，凝聚力很强。首先，血管紧张素II可能在很大程度上通过氧化和炎症机制导致高血压。第二，白介素10是一种重要的抗炎细胞因子，可以预防包括高血压在内的血管疾病。第三，先天免疫反应可能由非巨噬细胞血管细胞产生，并转导对多种炎症介质的免疫反应。第四，抗氧化机制的损害，包括细胞外和锰超氧化物歧化酶，在血管疾病中可能是非常重要的。第五，动脉粥样硬化小鼠血栓形成的加速是由于血栓调节蛋白氧化失活和抗凝蛋白C活性降低所致。第六，过氧化物酶体增殖物激活受体γ可能通过激活和抑制血管壁靶基因来调节血管功能和动脉粥样硬化的形成。该方案包括四个项目和一个行政核心，其中包括生物信息学部分。研究人员在每个项目中都整合了药理学方法、最先进的分子方法、复杂的小鼠生理测量方法和新的基因改变小鼠。在出色的环境下，调查人员之间的密切合作，持续保持着出色的生产率记录。该计划的长期目标是帮助更好地了解血管疾病的氧化和炎症机制，使之能够转化为动脉粥样硬化和其他血管疾病的改进治疗。

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.