Oxidation in Inflammation and Cardiovascular Disease

 描述(由申请人提供)：这个持续项目的总体目标是更好地了解氧化和炎症与心血管疾病(CVD)的联系机制。项目的重点是阐明心血管疾病期间涉及氧化和炎症的不同但相互关联的通路的机制，以及负责消解炎症反应的止血机制的破坏。该方案项目由高生产率和经验丰富的调查人员领导，由3个相互关联的项目和4个核心组成。项目1探索了髓过氧化物酶(MPO)和对氧磷酶1(PON1)之间潜在的相互调节作用，MPO是一种产生白细胞衍生的血红素蛋白的氧化剂，一旦释放，它就停留在高密度脂蛋白(高密度脂蛋白)上，对氧磷酶1(PON1)是一种促进全身抗氧化和动脉粥样硬化保护作用的高密度脂蛋白相关蛋白。在小鼠和人类中进行的生化和遗传学研究探索了缺血后动脉壁和心肌组织中MPO-PON1相互作用的功能重要性。项目2在主题上与项目1和项目3相关联，并探索位点特异性S亚硝化介导的步态(干扰素-伽马激活的翻译抑制物)翻译控制系统失活的作用，步态是限制炎症过程的途径。项目2类似地将其研究扩展到动脉粥样硬化期间的动脉壁，并通过心血管疾病的临床调查扩展到人类。探讨了炎症、动脉粥样硬化和心血管疾病过程中，血浆中MPO产生的特定氧化磷脂、清道夫受体CD36以及GAPDH和其他选定靶点的S亚硝化在步态系统失活过程中的作用。项目3与项目1和项目2类似，并建议研究纤溶酶原(PLG)如何与多种不同的PLG受体相互作用，通过涉及5-脂氧合酶的诱导和清道夫受体CD36的转录调节的途径，影响炎症反应、吞噬、胆固醇沉积和泡沫细胞形成过程中的巨噬细胞募集。脂蛋白(A)，一种模拟PLG的分子，在影响PLG依赖的巨噬泡沫细胞形成中的作用，以及CD36和氧化脂质的参与，也将被探索。三个科学核心(人类临床材料和蛋白质工程、质谱学和生物物理学以及动物模型)和一个管理核心提供多项目支持，大大加强了整个研究计划。拟议的计划项目将使人们更好地了解正常和疾病过程中的氧化和炎症途径，并可能有助于开发新的心血管疾病和心力衰竭风险评估工具和治疗方法。(摘要结束) 个别项目和核心单位 项目1：氧化应激与心血管疾病 (黑森，赤柱)

 DESCRIPTION (Provided by applicant): The overall goal of this continuing Program Project is to develop a better understanding of mechanisms linking oxidation and inflammation to cardiovascular disease (CVD). Projects focus on elucidating mechanisms of distinct yet interconnecting pathways involving both oxidation and inflammation during CVD, and the disruption of hemostatic mechanisms responsible for resolution of inflammatory responses. The Program Project is led by highly productive and experienced investigators and is comprised of 3 interrelated projects and 4 cores. Project 1 explores potential reciprocal regulatory interactions between myeloperoxidase (MPO), an oxidant generating leukocyte-derived heme protein that once released resides on the high density lipoprotein (HDL), and paraoxonase 1 (PON1), an HDL-associated protein that promotes systemic anti-oxidant and atheroprotective effects. Biochemical and genetic studies in mice and humans explore the functional importance of MPO - PON1 interactions in the artery wall and within myocardial tissues following ischemia. Project 2 is thematically linked to both Projects 1 and 3, and explores the role of site-specific S nitrosylation-mediated inactivation of the GAIT (IFN-Gamma-Activated Inhibitor of Translation) translational control system, a pathway limiting inflammation processes. Project 2 similarly extends its studies into the artery wall during atherosclerosis, and into humans through clinical investigations of CVD. It explores the role of MPO-generated specific oxidized phospholipids in plasma, scavenger receptor CD36, and site specific S-nitrosation of GAPDH and other selected targets during GAIT system inactivation during inflammation, atherosclerosis and CVD. Project 3 is similarly interrelated to Projects 1 and 2, and proposes to study how plasminogen (Plg) interacts with multiple distinct Plg receptors to influence macrophage recruitment during inflammatory responses, phagocytosis, and cholesterol deposition and foam cell formation via a pathway that involves induction of 5- lipoxygenase and transcriptional regulation of scavenger receptor CD36. The role of lipoprotein (a), a molecular mimic of Plg, in influencing Plg dependent macrophage foam cell formation, along with the involvement of CD36 and oxidized lipids, will also be explored. Three scientific cores (Human Clinical Materials & Protein Engineering, Mass Spectrometry & Biophysics, and Animal Models) and an Administrative Core, provide multi-project support, significantly strengthening the entire research program. The proposed Program Project will yield greater understanding of oxidative and inflammatory pathways in normal and disease processes, and may help develop new CVD and heart failure risk assessment tools and therapies. (End of Abstract) INDIVIDUAL PROJECTS AND CORE UNITS PROJECT 1:Oxidant Stress and Cardiovascular Disease (Hazen, Stanley)