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型糖尿病的主要致病因素。胰岛素抵抗和代谢综合征似乎是致病过程的根源。在这笔SCCOR赠款中，我们联合了不同研究领域的重要新发现，以确定将炎症作为治疗目标是否提供了治疗CHD的新途径。我们将通过生活方式干预，间接使用PPARa激动剂，并直接通过抑制炎症的主开关--核因子-KB途径来针对炎症。我们将把这些新的系列干预措施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血管成像(MDCTA)相结合，该技术可以检查冠状动脉循环中的动态过程，包括软斑块和硬斑块的发展和消退。具体目标包括：Shoelson的项目：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。我们发现，肥胖通过核因子-KB激活脂肪和肝脏的亚急性炎症过程，导致细胞因子的产生，并导致全身性胰岛素抵抗。我们假设，肥胖驱动的这些细胞因子的产生会促进CHD，并将在相关的啮齿动物模型中进行测试。在一系列三个临床项目中，我们将使用不同的干预措施来针对已确诊的冠心病患者的亚急性炎症，并评估干预措施对MDCTA评估的软斑块消退的影响。韦尔蒂的项目：由于西方饮食和肥胖激活了核因子-KB级联反应，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的消退，在戈德法布的项目中：我们将直接针对炎症信号

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