Oxidation in Inflammation and Cardiovascular Disease

 描述（由申请人提供）：该持续计划项目的总体目标是更好地了解将氧化和炎症与心血管疾病（CVD）联系起来的机制。项目重点在于阐明CVD期间涉及氧化和炎症的独特但相互关联的途径的机制，以及负责炎症反应解决的止血机制的破坏。该计划项目由富有成效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探索髓过氧化物酶（MPO）和对氧磷酶1（PON 1）之间潜在的相互调节相互作用，髓过氧化物酶（MPO）是一种氧化剂，产生白细胞衍生的血红素蛋白，一旦释放，就存在于高密度脂蛋白（HDL）上，对氧磷酶1（PON 1）是一种HDL相关蛋白，促进全身抗氧化和动脉粥样硬化保护作用。在小鼠和人类中进行的生化和遗传研究探索了缺血后动脉壁和心肌组织中MPO -PON 1相互作用的功能重要性。项目2与项目1和项目3在主题上相关，并探讨了位点特异性S亚硝酰化介导的GAIT（IFN-γ激活的翻译抑制剂）翻译控制系统失活的作用，这是一种限制炎症过程的途径。项目2同样将其研究扩展到动脉粥样硬化期间的动脉壁，并通过CVD的临床研究扩展到人类。它探讨了MPO产生的特定氧化磷脂在血浆中的作用，清道夫受体CD 36，GAPDH和其他选定的目标在炎症，动脉粥样硬化和CVD期间GAIT系统失活的位点特异性S-亚硝基化。项目3与项目1和项目2类似地相互关联，并提出研究纤溶酶原（Plg）如何与多种不同的Plg受体相互作用，以通过涉及5-脂氧合酶诱导和清道夫受体CD 36转录调节的途径影响炎症反应、吞噬作用、胆固醇沉积和泡沫细胞形成期间的巨噬细胞募集。还将探讨脂蛋白（a）（Plg的分子模拟物）在影响Plg依赖性巨噬细胞泡沫细胞形成中的作用，沿着CD 36和氧化脂质的参与。三个科学核心（人类临床材料与蛋白质工程，质谱与生物物理学和动物模型）和一个行政核心，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CVD和心力衰竭风险评估工具和疗法。(End摘要） 个别项目和核心单位 项目1：氧化应激与心血管疾病 （哈岑，斯坦利）

 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)