Metabolic Syndrome, Inflammation and Vascular Remodeling

代谢综合征、炎症和血管重塑

• 批准号: 7067756
• 负责人: FRANCINE K WELTY
• 金额: $ 271.13万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7067756
• 关键词: atherosclerosis; clinical research; coronary disorder; human subject; inflammation; metabolic syndrome; patient oriented research

DESCRIPTION (provided by applicant): "Metabolic Syndrome, Inflammation, and Vascular Remodeling" is the central theme of this SCCOR. Inflammation is increasingly accepted as a major contributor to the pathogenesis of coronary heart disease (CHD) and type 2 diabetes. Insulin resistance and the metabolic syndrome appear to be at the root of the pathogenic process. In this SCCOR grant we have united important new discoveries in diverse areas of research to determine whether primary targeting of inflammation as a therapeutic goal provides a new route to treat CHD. We will target inflammation via lifestyle intervention, indirectly using PPARa agonists, and directly by inhibiting the NF-KB pathway, the master switch of inflammation. We will combine these novel series of interventions with a newly developing, state-of-the-art, minimally invasive imaging technique, multidetector computed tomographic angiography (MDCTA) that examines dynamic processes in the coronary circulation, including the development and regression of soft and hard plaques. Specific Aims include: Project by Shoelson: To determine how obesity- and Western diet-induced inflammation influences CHD in animal models. We have discovered that obesity activates a subacute inflammatory process in fat and liver via NF-KB, which leads to the production of cytokines and causes systemic insulin resistance. We have hypothesized that the obesity-driven production of these cytokines promotes CHD and will test this in relevant rodent models. In a series of three clinical projects we will use different interventions to target subacute inflammation in patients with established CHD and assess the effect of the interventions on regression of soft plaque assessed by MDCTA. Project by Welty: Since Western diet and obesity activate the NF-KB cascade, we hypothesize that weight loss achieved through dietary and exercise intervention will suppress the subacute inflammatory process to promote vascular remodeling and regression of soft plaque, and in Project by Goldfarb: We will directly target the inflammatory signaling

描述（由申请人提供）： “代谢综合征、炎症和血管重塑”是本次 SCCOR 的中心主题。炎症越来越被认为是冠心病 (CHD) 和 2 型糖尿病发病机制的主要促成因素。胰岛素抵抗和代谢综合征似乎是致病过程的根源。在这项 SCCOR 资助中，我们整合了不同研究领域的重要新发现，以确定以炎症为主要治疗目标是否为治疗先心病提供了新途径。我们将通过生活方式干预、间接使用 PPARa 激动剂以及直接抑制 NF-KB 通路（炎症的主开关）来靶向炎症。我们将把这些新颖的干预措施与新开发的、最先进的微创成像技术、多排计算机断层扫描血管造影（MDCTA）相结合，该技术可检查冠状循环的动态过程，包括软斑块和硬斑块的形成和消退。具体目标包括： Shoelson 的项目：确定肥胖和西方饮食引起的炎症如何影响动物模型中的冠心病。我们发现肥胖通过 NF-KB 激活脂肪和肝脏中的亚急性炎症过程，从而导致细胞因子的产生并导致全身胰岛素抵抗。我们假设肥胖驱动的这些细胞因子的产生会促进冠心病，并将在相关的啮齿动物模型中对此进行测试。在一系列的三个临床项目中，我们将使用不同的干预措施来针对已确诊的 CHD 患者的亚急性炎症，并评估干预措施对 MDCTA 评估的软斑块消退的效果。 Welty 的项目：由于西方饮食和肥胖激活了 NF-KB 级联，我们假设通过饮食和运动干预实现的减肥将抑制亚急性炎症过程，促进血管重塑和软斑块消退，而 Goldfarb 的项目：我们将直接针对炎症信号传导