Diverse Roles of Reactive Oxygen Species and Inflammation in Vascular Disease

活性氧和炎症在血管疾病中的多种作用

• 批准号: 8507552
• 负责人: Kathy K Griendling
• 金额: $ 219.71万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-13 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507552
• 关键词: Address; Adoptive Transfer; Advanced Glycosylation End Products; Agonist; Angiotensin II; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antihypertensive Agents; Antioxidants; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Attention; Binding; Biology; Blood Pressure; Blood Vessels; Cell Adhesion Molecules; Cell Culture Techniques; Cell Nucleus; Cell Survival; Cell physiology; Cells; Chronic; Commit; Confocal Microscopy; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Disease; Disease model; Dose; Down-Regulation; Endothelial Cells; Endothelium; Environment; Equilibrium; Event; Future; Gene Expression; Genetically Modified Animals; Genotype; Goals; Growth; Growth Factor; Health; Hindlimb; Histology; Home environment; Homing; Hormonal; Hormones; Hyperglycemia; Hypertension; Image; Immunization; Impairment; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Interdisciplinary Study; Interleukin-17; Ischemia; Knockout Mice; Lead; Lesion; Link; Macrophage Activation; Matrix Metalloproteinases; Measurement; Measures; Mediating; Mediator of activation protein; Metabolic; Microscopy; Modeling; Molecular; Mus; NADPH Oxidase; Organism; Oxidative Stress; Pathology; Pathway interactions; Physiological; Platelet-Derived Growth Factor; Play; Predisposition; Process; Production; Qualifying; Reactive Oxygen Species; Receptor Cell; Regulation; Relaxation; Renal function; Research; Research Design; Research Personnel; Rodent; Role; Scientist; Signal Transduction; Signaling Molecule; Signaling Protein; Small Interfering RNA; Smooth Muscle Myocytes; Source; Stimulus; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Tissues; Translating; Tumor Necrosis Factor-alpha; Vascular Diseases; Work; abstracting; attenuation; base; bone morphogenetic protein receptor type II; bone morphogenetic protein receptors; bone morphogenic protein; cell growth; cell type; cytokine; diabetic; experience; hemodynamics; human TNF protein; improved; in vivo; inflammatory marker; insight; interest; macrophage; migration; monocyte; novel; oxidant stress; pathogen; programs; protective effect; protein function; receptor; repaired; response; response to injury; scaffold; shear stress; therapeutic target; vascular inflammation; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): For the past 17 years, investigators at Emory have been studying the sources, regulation and functional implications of reactive oxygen species (ROS) and inflammation in vascular biology and disease. Our PPG application builds on this expertise to test the overall hypothesis that ROS within the vessel wall lead to inflammatory processes that are central mediators of vascular disease. In project 1, Dr. David Harrison proposes that pre-activation of T-cells augments hypertension and will investigate the role of these cells in modulating vascular renal function. He will also study the role of IL-17 in mediating this effect, and test the antihypertensive potential of two therapies to inhibit T cell activation and homing. In project 2, Dr. Hanjoong Jo will investigate an exciting new hypothesis that loss of the bone morphogenic protein type II receptor (BMPRII), such as occurs in response to the inflammatory cytokine TNF-a, unleashes signaling proteins that are normally bound to the receptor and kept inactive, resulting in an uncontrolled activation of inflammatory pathways and the development of atherosclerosis. Dr. Jo will combine cell culture studies aimed at defining the mechanism underlying BMPRII regulation with studies using newly created, endothelial-specific BMPRlT'" ApoE'' mice to test these mechanisms in vivo. In project 3, Dr. W. Robert Taylor will examine the overall role of the receptor for advanced glycation end products (RAGE) in inhibiting collateral vessel formation in normal and diabetic conditions, focusing on the specific contributions of RAGE in monocytes and T cells, which are critical for the formation of collateral blood vessels. Additional studies will examine the ROS-dependent signaling to inflammatory gene expression, migration and cell viability. Project 4 will be directed by Dr. Kathy Grlendling, who proposes to study the differential roles of the NADPH oxidases Noxl and Nox4 in collateral formation and neointimal growth after vascular injury. This project includes studies designed to understand the mechanisms responsible for the opposite regulation of Noxl and Nox4, as well as the role of Nox4 in mediating the protective effects of BMP4. Dr. Grlendling will make use of Noxl and Nox4 knockout mice to investigate the function of these proteins in vivo. Four cores will support these projects. An administrative core, led by Dr. Grlendling, will provide administrative support for the program. A ROS core, led by Dr. Sergey Dikalov, will support state-of-the-art measurements of ROS, and a microscopy and histology core directed by Dr. Lula Hilenski will furnish expertise in confocal microscopy and imaging of inflammatory markers and ROS in cells and tissues. Finally, Dr. Bernard Lass^gue will lead an animal core to centralize rodent genotyping and husbandry. Overall, this research program will provide substantial new information defining the integrated mechanisms by which ROS and inflammation contribute to vascular disease. Ultimately, this research may establish new unifying concepts linking conditions that alter vascular oxidant stress and inflammation to the molecular processes underlying vasculopathies. (End of Abstract)

描述（由申请人提供）： 在过去的 17 年里，埃默里大学的研究人员一直在研究血管生物学和疾病中活性氧 (ROS) 和炎症的来源、调节和功能影响。我们的 PPG 应用程序建立在这种专业知识的基础上，来测试血管壁内的 ROS 导致炎症过程的总体假设，而炎症过程是血管疾病的核心介质。在项目 1 中，David Harrison 博士提出 T 细胞的预激活会加剧高血压，并将研究这些细胞在调节血管肾功能中的作用。他还将研究 IL-17 在介导这种作用中的作用，并测试两种疗法抑制 T 细胞激活和归巢的抗高血压潜力。在项目 2 中，Hanjoong Jo 博士将研究一个令人兴奋的新假设，即骨形态发生蛋白 II 型受体 (BMPRII) 的丧失（例如响应炎症细胞因子 TNF-a 而发生）会释放通常与受体结合并保持非活性的信号蛋白，导致炎症途径不受控制的激活和动脉粥样硬化的发展。 Jo 博士将把旨在定义 BMPRII 调节机制的细胞培养研究与使用新创建的内皮特异性 BMPRlT'" ApoE'' 小鼠的研究结合起来，在体内测试这些机制。在项目 3 中，W. Robert Taylor 博士将检查晚期糖基化终末产物 (RAGE) 受体在正常和糖尿病条件下抑制侧支血管形成的总体作用，重点关注 研究 RAGE 在单核细胞和 T 细胞中的具体贡献，这些细胞对于侧支血管的形成至关重要。其他研究将检查 ROS 依赖性信号传导对炎症基因表达、迁移和细胞活力的影响。项目 4 将由 Kathy Grlendling 博士领导，她提议研究 NADPH 氧化酶 Noxl 和 Nox4 在血管成形术后侧支形成和新内膜生长中的不同作用 受伤。该项目包括旨在了解 Nox1 和 Nox4 反向调节机制的研究，以及 Nox4 在介导 BMP4 保护作用中的作用。 Grlendling 博士将利用 Nox1 和 Nox4 敲除小鼠来研究这些蛋白质的体内功能。四个核心将支持这些项目。由 Grlendling 博士领导的行政核心将为该计划提供行政支持。活性氧 由 Sergey Dikalov 博士领导的核心将支持最先进的 ROS 测量，由 Lula Hilenski 博士领导的显微镜和组织学核心将提供共聚焦显微镜以及细胞和组织中炎症标记物和 ROS 成像的专业知识。最后，Bernard Lassgue 博士将领导一个动物核心中心，集中开展啮齿动物基因分型和饲养工作。总体而言，该研究计划将提供大量新信息来定义 ROS 和炎症导致血管疾病的综合机制。最终，这项研究可能会建立新的统一概念，将改变血管氧化应激和炎症的条件与血管病的分子过程联系起来。 （摘要完）