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

摘要-项目1 定义在心脏代谢疾病中调节器官内和器官间通讯的因素/途径是 追求这个PPG的每个项目。与P2和P3合作，P1将全面调查 热量限制和随后体重恢复的常见临床发现的分子机制 (as在“溜溜球”节食中）分别解决和加剧斑块中的代谢性炎症、eWAT和 肝脏目的是确定肥胖和IR中的适应不良通路以及中断它们的策略， 促进动脉粥样硬化、肥胖和NAFLD/NASH中的炎症消退和组织稳态。P1将 包括临床样本的研究，并将组学数据与人类数据集相结合， 概述的模型与人类心脏代谢疾病的相关性，以及提示分子 人类数据背后的机制。由于LXRα的磷酸化形式占据了启动子， P1-P3中正在研究的多个基因，我们的报告表明，不能磷酸化LXRα全球 减弱NASH，我们也有动机确定细胞类型和转录调控 对肝脏有显著的益处。 因此，P1中有两个目标： 目的1：确定热量限制（CR）解决动脉粥样硬化斑块的机制， eWAT炎症，以及这些好处是如何在体重反弹时失去的。 目的2：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同的互补性， 检查在人体组织和人类转录组数据库，P1将有助于本计划项目的 我们的目标是发现新的机制见解，从而导致治疗方法，以消除夸大的 巨噬细胞积聚、炎症和器官内/器官间通信，这些都增加了心血管风险。

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.