Metabolic Syndrome, Inflammation and Vascular Remodeling

描述（由申请人提供）： “代谢综合征、炎症和血管重塑”是本SCCOR的中心主题。炎症越来越被认为是冠心病和2型糖尿病发病机制的主要因素。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，我们联合了不同研究领域的重要新发现，以确定是否将炎症作为治疗目标的主要靶点提供了治疗CHD的新途径。我们将通过生活方式干预来靶向炎症，间接使用PPARa激动剂，直接通过抑制炎症的主开关NF-κ B通路。我们将联合收割机这些新的系列干预与一种新开发的、最先进的微创成像技术--多探测器计算机断层扫描血管造影术（MDCTA）相结合，该技术可检查冠状动脉循环中的动态过程，包括软硬斑块的发展和消退。具体目标包括：Shoelson项目：确定肥胖和西方饮食诱导的炎症如何影响动物模型中的CHD。我们已经发现，肥胖通过NF-κ B激活脂肪和肝脏中的亚急性炎症过程，这导致细胞因子的产生并引起全身性胰岛素抵抗。我们假设肥胖驱动的这些细胞因子的产生促进CHD，并将在相关啮齿动物模型中测试这一点。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影响。关于Welty：由于西方饮食和肥胖激活NF-κ B级联反应，我们假设通过饮食和运动干预实现的体重减轻将抑制亚急性炎症过程，促进血管重塑和软斑块消退，并在Goldfarb的项目中：我们将直接靶向炎症信号传导。

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