SCCOR in Metabolic Syndrome and Vascular Disease

描述（由申请人提供）： 代谢综合征存在于近四分之一的美国成年人中，并与过早的血管疾病有关，使其成为21世纪世纪最重要的公共卫生问题之一。我们建议在华盛顿大学建立一个血管损伤、修复和重塑的临床导向研究专业中心。我们SCCOR的中心主题是定义代谢综合征与动脉粥样硬化血管疾病之间的生理、细胞和分子机制，并迅速应用这些信息来改变代谢综合征患者的护理。代谢综合征的特征是肥胖，胰岛素抵抗和炎症，但这些条件如何导致血管疾病以及体重减轻是否影响潜在机制尚不清楚。我们将通过六个涉及人类的互动项目，将基本的机械观察转化为对代谢综合征患者的改善护理。在项目1中，我们研究了通过使用新的抗炎策略来调节代谢综合征中的遗传毒性应激的可行性。在项目2中，我们通过研究炎症、循环修复细胞和手术修复后动脉瘤持续扩张之间的关系来定义综合征如何影响主动脉瘤，并将项目1的新型抗炎策略扩展到动脉瘤生物学。在项目3中，我们阐明了炎症信号通路在与代谢综合征相关的动脉粥样硬化中的作用，以及体重减轻在这些通路中的作用。在项目4中，我们确定减肥饮食中的碳水化合物含量是否会影响代谢综合征的全身炎症和内皮功能。在项目5中，我们将巨噬细胞衍生的氧固醇与动脉粥样硬化的炎症联系起来，并确定循环氧固醇是否是代谢综合征中受体重减轻影响的血管疾病的新生物标志物。在项目6中，我们研究了骨桥蛋白基因与代谢综合征炎症相关的血管重塑之间的关系，并描述了体重减轻如何影响这种关系。我们的长期目标是通过创建一个转化框架来产生血管疾病的新疗法，从而改善代谢综合征患者的生活质量。本申请中描述的多学科方法可能降低近5000万患有代谢综合征的美国人中由血管疾病引起的发病率和死亡率。

DESCRIPTION (provided by applicant): The metabolic syndrome is present in nearly a quarter of American adults and is associated with premature vascular disease, making it one of the most important public health problems of the 21st century. We propose to establish a Specialized Center of Clinically Oriented Research (SCCOR) in Vascular Injury, Repair, and Remodeling at Washington University. The central theme of our SCCOR is to define the physiological, cellular and molecular mechanisms linking metabolic syndrome with atherosclerotic vascular disease and rapidly apply this information to transform the care of people with the metabolic syndrome. The metabolic syndrome is characterized by obesity, insulin resistance and inflammation, but how these conditions cause vascular disease and whether weight loss affects the underlying mechanisms are unknown. We will translate fundamental mechanistic observations into improved care for people with the metabolic syndrome through six interactive projects involving humans. In Project 1, we examine the feasibility of modulating genotoxic stress in the metabolic syndrome by using a new anti-inflammatory strategy. In Project 2, we define how the syndrome affects aortic aneurysms by studying the relationships between inflammation, circulating reparative cells, and persistent aneurysm expansion following surgical repair and extend the novel anti-inflammatory strategy of Project 1 to aneurysm biology. In Project 3, we elucidate the role of inflammatory signaling pathways in atherosclerosis associated with the metabolic syndrome and the role of weight loss in these pathways. In Project 4, we determine if the carbohydrate content of weight loss diets affects systemic inflammation and endothelial function in the metabolic syndrome. In Project 5, we implicate macrophage-derived oxysterols in the inflammation of atherosclerosis and determine if circulating oxysterols are novel biomarkers for vascular disease affected by weight loss in the metabolic syndrome. In Project 6, we examine the relationships between the osteopontin gene and vascular remodeling associated with inflammation in metabolic syndrome and characterize how thBse relationships are affected by weight loss. Our long term objective is to improve the quality of life for people with the metabolic syndrome by creating a translational framework to generate novel treatments for vascular disease. The multidisciplinary approach described in this application is likely to decrease the morbidity and mortality caused by vascular disease in the nearly 50 million Americans with metabolic syndrome.