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 定义调节心脏代谢性疾病内部内部和器官间通信的因素/途径是 追求该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的常见临床发现的分子机制 （如“溜溜球”节食中）分别解决斑块，ewat和 肝。目的是确定肥胖和红外适应不良的途径以及打断它们的策略，以便 促进动脉粥样硬化，肥胖和NAFLD/NASH的炎症分辨率和组织稳态。 P1会 包括临床样本的研究和与人类数据集的综合数据集，以估计临床 概述模型与人类心脏代谢疾病的相关性，并暗示分子 人类数据的基础机制。鉴于LXRα的磷酸化形式占据了启动子 P1-P3中研究的多个基因，我们的报告表明，全球磷酸化LXRα的磷酸化无法 nash衰减，我们也有动力确定细胞类型和转录调节 负责肝脏中的这一显着利益。 这是P1中有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，以及体重恢复后如何减轻这些好处。 目标2：确定CR和LXRα磷酸化对NASH的影响。 像其他项目一样，通过采用最先进的方法和共享的完成 在人体组织和人类转录组数据库中的检查，P1将有助于该计划项目的 目的是发现新的机械见解，这些见解导致治疗方法来消除夸张 巨噬细胞的积累，感染和内部/器官间通信，以扩大心血管风险。