Oxidation in Inflammation and Cardiovascular Disease

炎症和心血管疾病中的氧化

• 批准号: 9266478
• 负责人: Stanley L Hazen
• 金额: $ 184.89万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266478
• 关键词: Acute; Animal Model; Antibodies; Antioxidants; Arachidonate 5-Lipoxygenase; Area; Arteries; Arylesterase; Assessment tool; Atherosclerosis; Biochemical; Biochemical Genetics; Biocompatible Materials; Biometry; Biophysics; Blood Vessels; Bone Marrow Transplantation; CD36 gene; Calgranulin A; Cardiac; Cardiovascular Diseases; Cell Separation; Cells; Cephalic; Cholesterol; Chronic; Clinical; Data; Deposition; Deuterium; Disease; Disease model; Echocardiography; Enzymes; Fertilization; Foam Cells; Foxes; Genetic; Genetic Determinism; Genetic study; Goals; Heart failure; Hematopoietic stem cells; Hemeproteins; Hemostatic Agents; High Density Lipoproteins; Human; Hydrogen; Inflammation; Inflammation Process; Inflammatory; Inflammatory Response; Injury; Interferon Type II; Ischemia; Lesion; Leukocytes; Link; Lipoprotein (a); Mass Spectrum Analysis; Mediating; Modeling; Molecular; Mus; Myocardial; Myocardial Infarction; Myocardial tissue; Myocardium; NOS2A gene; Nitrosation; Operative Surgical Procedures; Outcome; Oxidants; Oxides; Participant; Pathway interactions; Patients; Performance; Peroxidases; Phagocytosis; Phospholipids; Plant Roots; Plasma; Plasminogen; Post-Translational Protein Processing; Process; Protein Engineering; Protein S; Proteins; Proteomics; Recruitment Activity; Reproducibility; Research; Research Personnel; Resolution; Risk Assessment; Role; S100A8 gene; S100A9 gene; Sampling; Serum Markers; Services; Site; Specimen; Stimulus; System; Techniques; Testing; Therapeutic Agents; Tissues; Training; Transcriptional Regulation; Translations; Venous blood sampling; Ventricular Remodeling; atheroprotective; biophysical model; biophysical techniques; clinical investigation; clinical material; experience; in vivo; inhibitor/antagonist; injury and repair; macrophage; mouse model; oxidant stress; oxidation; oxidized lipid; physical property; plasminogen receptor; programs; scavenger receptor; small molecule; tool; vascular inflammation

 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.

 描述（由申请人提供）：该持续计划项目的总体目标是更好地理解氧化和炎症与心血管疾病 (CVD) 之间的联系机制。项目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途径的机制，以及负责解决炎症反应的止血机制的破坏。该计划项目由高产且经验丰富的研究人员领导，由 3 个相互关联的项目和 4 个核心组成。项目 1 探讨了髓过氧化物酶 (MPO) 和对氧磷酶 1 (PON1) 之间潜在的相互调节相互作用。髓过氧化物酶 (MPO) 是一种产生氧化剂的白细胞来源的血红素蛋白，一旦释放，就会驻留在高密度脂蛋白 (HDL) 上，而对氧磷酶 1 (PON1) 是一种 HDL 相关蛋白，可促进全身抗氧化和动脉粥样硬化作用。对小鼠和人类进行的生化和遗传学研究探讨了缺血后动脉壁和心肌组织内 MPO - PON1 相互作用的功能重要性。项目 2 在主题上与项目 1 和 3 相关，探讨位点特异性 S 亚硝基化介导的 GAIT（IFN-γ 激活翻译抑制剂）翻译控制系统失活的作用，该系统是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。它探讨了炎症、动脉粥样硬化和 CVD 期间 GAIT 系统失活期间 MPO 生成的特异性氧化磷脂在血浆中的作用、清道夫受体 CD36 以及 GAPDH 和其他选定靶标的位点特异性 S 亚硝化作用。项目 3 与项目 1 和 2 类似地相互关联，并提议研究纤溶酶原 (Plg) 如何与多种不同的 Plg 受体相互作用，通过涉及 5-脂氧合酶诱导和清道夫受体 CD36 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过程中巨噬细胞的募集。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，以及 CD36 和氧化脂质的参与。三个科学核心（人类临床材料和蛋白质工程、质谱和生物物理学以及动物模型）和一个行政核心提供多项目支持，显着加强了整个研究计划。拟议的项目将加深对正常和疾病过程中氧化和炎症途径的了解，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疗法。