Diverse Roles of Reactive Oxygen Species and Inflammation in Vascular Disease

 描述（由申请人提供）：本研究项目的总体目标是深入了解活性氧（ROS）和炎症单独或共同介导正常血管功能和血管疾病的常见细胞和分子机制。虽然ROS是正常代谢功能和细胞活力所必需的，但过量的ROS或抗氧化防御减弱可导致病理生理事件。类似地，虽然单核细胞和巨噬细胞介导愈合和新血管形成，但过度炎症导致动脉粥样硬化和高血压。在过去的25年里，我们的研究小组研究了血管系统中ROS产生和炎症的无数反应，并研究了它们在几乎所有主要血管疾病中的作用。在这 我们将在这些发现的基础上进行扩展，以更好地理解ROS和炎症对血管功能既必要又有害的机制，并开始探索靶向干预的治疗策略。在项目1中，Hanjoong Jo博士将探索促动脉粥样硬化微小RNA下调骨形态发生受体II（BMPR 2）的机制和后果，并将开发可以保护BMPR 2免受下调的靶点阻滞剂。在项目2中，Aloke Finn博士将研究一种新型的非泡沫细胞巨噬细胞，M（Hb）或Hb相关巨噬细胞，表达CD 163。他将测试这些新的巨噬细胞诱导斑块血管生成和增加巨噬细胞存活，促进高危斑块发展的假设。在项目3中，Kathy Griendling博士将研究Nox 4相关蛋白Poldip 2的功能和结构方面，该蛋白有助于基质调节和主动脉硬化，并将测试有针对性的治疗策略以防止动脉瘤形成。Alejandra San Martin博士也在项目4中研究Poldip 2，但着眼于了解其在线粒体动力学和增殖中的作用。最后，在项目5中，W。Robert Taylor将研究过氧化氢酶（一种调节血管壁硬度和动脉瘤形成的至关重要的抗氧化酶）的表达如何受PGC-1a通路或多态性的调节，并将测试过氧化氢酶表达抑制剂在治疗动脉瘤中的疗效。拟议的研究将得到医学核心显微镜主任Lula Hilenski博士和动物核心主任Bernard Lassègue博士的卓越合作专业知识的支持。虽然该计划的主要目标是了解疾病的基本机制，并开始将其转化为临床相关的应用，我们也致力于培训下一代研究人员，支持初级教师的职业生涯，并传播我们的研究结果，作为未来调查的重点。因此，PPG应用代表了在氧化应激、炎症和血管生物学方面具有丰富经验的高素质科学家之间独特的多学科合作，他们仍然致力于定义血管疾病的病理生理学基础。

 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.