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

解决动脉粥样硬化斑块和胰岛素抵抗其他部位的巨噬细胞炎症

• 批准号: 10616536
• 负责人: Edward A Fisher
• 金额: $ 52.8万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10616536
• 关键词: Acceleration; Adipocytes; Adipose tissue; Adverse effects; Anti-Inflammatory Agents; Appearance; Arterial Fatty Streak; Atherosclerosis; Attenuated; Bioinformatics; Body Weight decreased; Body mass index; Bone Marrow; Caloric Restriction; Cardiometabolic Disease; Cells; Chromatin; Clinical; Clinical Research; Collaborations; Communication; Conditioned Culture Media; Data; Data Set; Databases; Diet; Employment; Epidemic; Epigenetic Process; Event; Fatty Liver; Fibrosis; Functional disorder; Funding; Genes; Goals; Hematopoietic; Hematopoietic stem cells; Hepatic; Hepatocyte; Histology; Homeostasis; Human; IgG Receptors; Immune; Immunohistochemistry; Immunologics; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Insulin Resistance; Interruption; Kupffer Cells; LXRalpha protein; Liver; Macrophage; Measures; Metabolic; Metabolic syndrome; Modeling; Molecular; Monitor; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Hormone Receptors; Nuclear RNA; Obesity; Organ; Participant; Pathway interactions; Pattern; Phagocytes; Phosphorylation; Plasma; Prevalence; Proteomics; Reporting; Resolution; Risk; Risk Factors; Role; Sampling; Signal Transduction; Site; Testing; Therapeutic; Tissue Transplantation; Tissues; Training; Transcriptional Regulation; Transplantation; Weight; attenuation; base; cardiometabolism; cardiovascular risk factor; cell type; clinically relevant; comorbidity; dieting; extracellular vesicles; human data; human tissue; hypercholesterolemia; improved; insight; interest; non-alcoholic; non-alcoholic fatty liver disease; patient stratification; progenitor; programs; promoter; single-cell RNA sequencing; stellate cell; stem; trafficking; transcriptome; transcriptome sequencing; transcriptomics

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.

摘要 – 项目 1 定义调节心脏代谢疾病中器官内和器官间通讯的因素/途径 P1将与P2和P3合作，全面调查本次PPG的每个项目。 热量限制的分子机制以及随后体重恢复的常见临床发现 （如“溜溜球”节食）分别解决和恶化斑块、eWAT 和 目标是确定肥胖和 IR 的适应不良途径以及中断它们的策略，以便 促进动脉粥样硬化、肥胖和 NAFLD/NASH P1 中的炎症消退和组织稳态。 包括临床样本的研究，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疾病的相关性，以及建议分子 考虑到 LXRα 的磷酸化形式占据启动子，该机制是人类数据的基础。 P1-P3 中正在研究的多个基因，我们的报告表明无法全局磷酸化 LXRα NASH 减弱，我们也有动力确定细胞类型和转录调控 对肝脏有这种显着益处的原因。 因此，P1 有 2 个目标： 目标 1：确定热量限制 (CR) 解决动脉粥样硬化斑块和 eWAT 炎症，以及体重恢复后这些益处如何消失。 目标 2：确定 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进行检查，P1 将为本项目的 目标是发现新的机制见解，从而找到治疗方法来消除夸大的症状 巨噬细胞积聚、炎症和器官内/器官间通讯会增加心血管风险。