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: 9236298
• 负责人: Kathy K Griendling
• 金额: $ 6.82万
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9236298
• 关键词: Address; Aneurysm; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Antioxidants; Atherosclerosis; BMPR2 gene; Binding; Biology; Blood Vessels; Cardiovascular Diseases; Cell Adhesion Molecules; Cell Nucleus; Cell Survival; Cells; Collaborations; Development; Diabetic Angiopathies; Disease; Disease model; Down-Regulation; Endothelium; Event; Eye; Faculty; Future; Genetic Polymorphism; Goals; Healed; Health; Hypertension; Impairment; Individual; Inflammation; Interdisciplinary Study; Intervention; Investigation; Ischemia; Lead; Life; Matrix Metalloproteinases; Mediating; Medicine; Metabolic; MicroRNAs; Microscopy; Mitochondria; Molecular; Oxidative Stress; Pathway interactions; Peptides; Play; Process; Production; Proteins; Qualifying; Reactive Oxygen Species; Regulation; Relaxation; Research; Research Personnel; Role; Scientist; Site; Smooth Muscle; Smooth Muscle Myocytes; Testing; Therapeutic; Training; Translating; Treatment Efficacy; Vascular Diseases; Vascular Smooth Muscle; Work; abstracting; angiogenesis; antioxidant enzyme; base; bone; bone loss; bone morphogenic protein; career; catalase; cell growth; clinically relevant; design; experience; healing; high risk; inhibitor/antagonist; insight; interest; macrophage; mid-career faculty; migration; monocyte; new therapeutic target; next generation; novel; prevent; programs; receptor; response; response to injury; targeted treatment; vascular inflammation

 DESCRIPTION (provided by applicant): The overall goal of this research program is to gain insight into the common cellular and molecular mechanisms through which reactive oxygen species (ROS) and inflammation individually and together mediate normal vascular function and vascular disease. While ROS are required for normal metabolic function and cell viability, excessive ROS or weakened antioxidant defenses can lead to pathophysiological events. Similarly, while monocytes and macrophages mediate healing and new vessel formation, excess inflammation contributes to atherosclerosis and hypertension. Over the past 25 years, our research group has investigated the myriad responses to ROS production and inflammation in the vasculature and studied their roles in virtually all of the major vascular diseases. In this proposal, we will expand upon these findings to better understand the mechanisms by which ROS and inflammation are both necessary and detrimental to vascular function, and to begin to explore therapeutic strategies for targeted intervention. In Project 1, Dr. Hanjoong Jo will explore the mechanisms responsible for, and consequences of, downregulation of bone morphogenic receptor II (BMPR2) by pro-atherogenic microRNAs and will develop target site blockers that can protect BMPR2 from downregulation. In Project 2, Dr. Aloke Finn will study a new type of non-foam cell macrophage, M(Hb) or Hb- associated macrophage, that expresses CD163. He will test the hypothesis that these novel macrophages induce plaque angiogenesis and increase macrophage survival, promoting the development of high-risk plaques. In Project 3, Dr. Kathy Griendling will examine the functional and structural aspects of the Nox4- associated protein, Poldip2, that contribute to matrix regulation and aortic stiffening, and will tst targeted therapeutic strategies to prevent aneurysm formation. Dr. Alejandra San Martin is also studying Poldip2 in Project 4, but with an eye to understanding its role in mitochondrial dynamics and proliferation. Finally, in Project 5, Dr. W. Robert Taylor will investigate how the expression of catalase, a critically important antioxidant enzyme that modulates wall stiffness and aneurysm formation, is regulated by the PGC-1a pathway or polymorphisms, and will test inhibitors of catalase expression for their efficacy in treating aneurysms. The proposed studies will be supported by the exceptional collaborative expertise of Dr. Lula Hilenski, the director of the Microscopy in Medicine Core, and Dr. Bernard Lassègue, director of the Animal Core. While the major goal of the program is centered on understanding basic mechanisms of disease and beginning to translate them into clinically relevant applications, we are also dedicated to trainin the next generation of investigators, supporting the careers of junior faculty, and disseminating our findings to serve as a nidus for future investigation. This PPG application thus represents a distinctive multidisciplinary collaboration among highly qualified scientists with extensive experience in oxidative stress, inflammation and vascular biology who remain committed to defining the pathophysiologic basis of vascular disease.

 描述（由适用提供）：该研究计划的总体目标是深入了解反应性氧（ROS）（ROS）和炎症单独，正常血管功能和血管疾病的常见细胞和分子机制。正常代谢功能和细胞生存力需要ROS，但过多的ROS或抗氧化剂防御可能会导致病理生理事件。同样，虽然单核细胞和巨噬细胞培养基的愈合和新血管的形成超过注射促进动脉粥样硬化和高血压。在过去的25年中，我们的研究小组研究了对脉管系统中ROS产生和注射的无数反应，并研究了它们在几乎所有主要血管疾病中的作用。在这个 提案，我们将扩展这些发现，以更好地了解ROS和注射既需要又对血管功能有害的机制，并开始探索针对性干预的治疗策略。在项目1中，Hanjoong Jo博士将通过亲动脉粥样硬化的microRNA探索骨形态学受体II（BMPR2）的下调的机制和后果，并将开发可以保护BMPR2的目标位点阻滞剂，以保护BMPR2免受下调。在项目2中，Aloke Finn博士将研究一种表达CD163的新型非泡沫细胞巨噬细胞，M（HB）或与HB相关的巨噬细胞。他将检验以下假设：这些新型巨噬细胞诱导斑块血管生成并增加巨噬细胞的存活，从而促进高风险斑块的发展。在项目3中，Kathy Griendling博士将检查NOX4相关蛋白Poldip2的功能和结构方面，这些蛋白有助于基质调节和主动脉僵硬，并将针对靶向的治疗策略，以防止动脉瘤形成。 Alejandra San Martin博士还在项目4中研究Poldip2，但要了解其在线粒体动力学和扩散中的作用。最后，在项目5中，W。RobertTaylor博士将调查过氧化氢酶的表达是一种非常重要的抗氧化剂酶调节壁刚度和动脉瘤形成的表达如何受PGC-1A途径或多态性的调节，并将测试其在治疗动脉症方面的表达抑制剂。拟议的研究将得到医学核心显微镜主任卢拉·希伦斯基（Lula Hilenski）博士的卓越合作专业知识，而动物核心主任伯纳德·拉萨格（BernardLassègue）博士。尽管该计划的主要目标集中在理解疾病的基本机制上，并开始将其转化为临床上相关的应用，但我们也致力于培训下一代研究人员，支持初级教师的职业，并传播我们的发现，以作为Nidus的未来投资。因此，这种PPG的应用代表了在氧化应激，感染和血管生物学方面具有丰富经验的高素质科学家之间的独特多学科合作，他们仍然致力于定义血管疾病的病理生理基础。