Diverse Roles of Reactive Oxygen Species and Inflammation in Vascular Disease

 描述(由申请人提供)：本研究计划的总体目标是深入了解活性氧(ROS)和炎症单独或共同调节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存活所必需的，但过量的ROS或抗氧化剂防御能力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参与修复和新血管的形成，但过度的炎症会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对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 为了更好地理解ROS和炎症对血管功能既必要又有害的机制，我们将对这些发现进行扩展，并开始探索有针对性的干预治疗策略。在项目1中，Jo Hanjoong博士将探索促动脉粥样硬化的microRNAs下调骨形态发生受体II(BMPR2)的机制和后果，并将开发能够保护BMPR2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，它表达CD163。他将验证这一假说，即这些新型巨噬细胞诱导斑块血管生成并提高巨噬细胞存活率，从而促进高危斑块的发展。在项目3中，Kathy Griendling博士将研究NOX4相关蛋白Poldip2的功能和结构方面，它有助于基质调节和主动脉硬化，并将TST作为预防动脉瘤形成的有针对性的治疗策略。亚历杭德拉·圣马丁博士也在研究项目4中的Poldip2，但目的是了解它在线粒体动力学和增殖中的作用。最后，在项目5中，W.Robert Taylor博士将研究过氧化氢酶的表达如何受到PGC-1a途径或基因多态性的调节，并将测试过氧化氢酶表达抑制剂在治疗动脉瘤中的有效性。过氧化氢酶是一种至关重要的抗氧化酶，调节壁僵硬和动脉瘤形成。拟议的研究将得到医学核心显微镜主任卢拉·希伦斯基博士和动物核心主任伯纳德·拉塞格博士非凡的合作专业知识的支持。虽然该项目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生涯，并传播我们的发现，作为未来研究的难点。因此，这种PPG应用代表了在氧化应激、炎症和血管生物学方面拥有丰富经验的高素质科学家之间的独特的多学科合作，他们仍然致力于确定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.