Resolving Macrophage Inflammation in Atherosclerotic Plaques and Other Sites in Insulin Resistance

摘要-项目1 定义心脏代谢性疾病中调节器官内和器官间通讯的因素/途径是 对这个PPG的每一个项目的追求。与P2和P3合作，P1将全面调查 热量限制和随后体重回升的常见临床表现的分子机制 (如“溜溜球”节食)分别解决和加剧了斑块、eWAT和 肝脏。我们的目标是找出肥胖和胰岛素抵抗中的不适应途径，并采取策略来阻断它们，以便 促进动脉粥样硬化、肥胖和NAFLD/NASH的炎症消退和组织动态平衡。P1将 包括对临床样本的研究，并将组学数据与人类数据集相结合以估计临床 概述的模型与人类心脏代谢性疾病的相关性，以及建议的分子 人类数据背后的机制。鉴于LxRα的磷酸化形式占据了启动子 在P1-P3研究中的多个基因，我们的报告说，不能在全球范围内磷酸化LXRα 减毒NASH，我们也有动力来确定细胞类型和转录调控 对肝脏的这一显著益处负责。 因此，在P1中有两个目标： 目的1：确定卡路里限制(CR)消除动脉粥样硬化斑块和 EWAT炎症，以及这些好处是如何在体重恢复时消失的。 目的：探讨CR和LXRα磷酸化对NASH的影响。 与其他项目一样，通过采用最先进的方法和共享互补 在人体组织和人类转录组数据库中的检查，P1将为该计划项目的 目标是发现新的机制洞察力，导致治疗方法平息夸张 巨噬细胞堆积、炎症和器官内/器官间的沟通会放大心血管风险。

Summary – Project 1 Defining the factors/pathways that regulate intra- and inter-organ communications in cardiometabolic disease is a pursuit of each Project of this PPG. In collaboration with P2 and P3, P1 will comprehensively investigate molecular mechanisms by which caloric restriction and the common clinical finding of subsequent weight regain (as in “yo-yo” dieting) resolves and exacerbates, respectively, metabolic inflammation in plaques, eWAT, and liver. The goal is to identify maladaptive pathways in obesity and IR and strategies to interrupt them, in order to promote inflammation resolution and tissue homeostasis in atherosclerosis, obesity and NAFLD/NASH. P1 will include studies of clinical samples and integrate ‘omic data with human data sets to estimate the clinical relevance of the outlined models to human cardiometabolic disease, as well as to suggest molecular mechanisms underlying the human data. Given that the phosphorylated form of LXRα occupies the promoters of multiple genes under study in P1-P3, and our report that the inability to phosphorylate LXRα globally attenuated NASH, we are also motivated to determine the cell types and the transcriptional regulation responsible for this notable benefit in the liver. Thus, there are 2 Aims in P1: Aim 1: To determine the mechanisms by which caloric restriction (CR) resolves atherosclerotic plaque and eWAT inflammation, and how these benefits are lost upon weight regain. Aim 2: To determine the effects of CR and LXRα phosphorylation on NASH. Like the other Projects, through the employment of state-of-the-art approaches and shared complementary examinations in human tissues and human transcriptome databases, P1 will contribute to this Program Project’s goal to discover new mechanistic insights that lead to therapeutic approaches to quench the exaggerated macrophage accumulation, inflammation and intra/inter-organ communications that amplify cardiovascular risk.