Macrophage Dysfunction in Atherosclerosis and Cardiometabolic Diseases

动脉粥样硬化和心脏代谢疾病中的巨噬细胞功能障碍

基本信息

批准号：
10424900
负责人：
Edward A Fisher
金额：
$ 256.79万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/10424900
关键词：
Adipocytes Adipose tissue Adverse effects Arterial Fatty Streak Atherosclerosis Binding Biochemistry Bioinformatics Biological Availability Biometry Bone Marrow Breeding Caloric Restriction Cardiometabolic Disease Cardiovascular Diseases Cell Communication Cells Clinical Trials Communication Complex Cues Databases Deposition Diabetes Mellitus Employment Endotoxins Fostering Functional disorder Funding High Fat Diet Home Human Immune Immune response Inflammation Inflammatory Insulin Resistance Kupffer Cells LXRalpha protein Lead Lipids Liver Mediating Mediation Mediator of activation protein Metabolic Metabolic dysfunction Metabolism Molecular Mus Myelogenous NTN1 gene Nervous system structure Obesity Organ Pathologic Pathology Patients Pattern Phosphorylation Play Procedures Process Program Research Project Grants Regulation Resolution Signal Pathway Site Stimulus Therapeutic Thermogenesis Tissues Work atherosclerosis risk cardiometabolism cardiovascular disorder risk cardiovascular risk factor clinically significant comorbidity experience human tissue imprint in vivo inhibitor insight macrophage nonalcoholic steatohepatitis novel novel therapeutic intervention programs receptor recruit remediation response therapeutic target trafficking transcription factor transcriptome

项目摘要

Summary: Overall This Program Project grant has unveiled key roles for macrophage metabolism, depot- and cue-dependent molecular re-programming and intraorgan communications in cardiometabolic dysfunction. The Program Project team will build upon these discoveries and forge new directions. Macrophages mediate intraorgan communications and, through interorgan communications, macrophages and other bioactive mediators home to and infiltrate distinct sites, such as in the atherosclerotic plaque; in obese adipose tissue; and to be newly explored in this Cycle; in the liver. In cardiometabolic dysfunction, the liver is the recipient of increased endotoxin from the gut; accumulation of lipid from adipose tissue; and increased bioavailability of damage-associated molecular patterns. In each metabolic organ, the tissue-specific niche defines the myriad consequences, such as excess synthesis/deposition of pathological lipids; and recruitment of infiltrating bone marrow-derived immune cells. These delivered stimuli modulate endogenous signaling pathways in resident adipose tissue macrophages and liver Kupffer cells and impart immunometabolic imprints on macrophage subsets in atherosclerosis, obesity and non-alcoholic steatohepatitis (NASH). These concepts are clinically-significant, as atherosclerosis, obesity and NASH are established risk factors for cardiovascular diseases. The Program Project will explore three specific aims: First, Aim 1 (Project 1) will determine the mechanisms by which caloric restriction mediates macrophage intra- and interorgan communications in atherosclerosis, obesity and NASH, and define the impact of LXRα phosphorylation in liver immune cells on NASH-related factors under study in each Project. Second, Aim 2 (Project 2) will probe the mechanisms by which netrin-1 and its receptor network mediate macrophage intra- and interorgan communications in atherosclerosis, obesity and NASH. Third, Aim 3 (Project 3) will probe the mechanisms by which RAGE/DIAPH1 mediates macrophage intra- and interorgan communications in atherosclerosis, obesity and NASH. The Program Project will be supported by three cores: Core A (Administrative, which includes Biostatistics and Bioinformatics); Core B (Pathology and Biochemistry); and Core C (Mouse Breeding and Procedure Core). Collectively, this highly-motivated Program Project team continues to work together synergistically to interrogate novel mechanisms by which macrophage intraorgan and interorgan communications contribute to the mediation and remediation of cardiometabolic disease. Through the employment of state-of-the-art approaches and shared complementary examinations in human tissues and human transcriptome databases, this Program Project will discover new mechanistic insights that lead to therapeutic approaches to quench the exaggerated macrophage accumulation, inflammation and intra/interorgan communications that amplify cardiovascular risk.

总结：总体该计划项目拨款揭示了巨噬细胞代谢、储存库和线索依赖性的关键作用心脏代谢功能障碍的分子重编程和器官内通讯。团队将在这些发现的基础上开拓新的方向。通讯，并通过器官间通讯，巨噬细胞和其他生物活性介质并渗透到不同的部位，例如肥胖脂肪组织中的动脉粥样硬化斑块；在这个循环中探索；在心脏代谢功能障碍中，肝脏是内毒素增加的接受者。来自肠道；脂肪组织中脂质的积累；以及与损伤相关的生物利用度的增加；在每个代谢器官中，组织特异性生态位定义了无数的后果，例如病理性脂质的过度合成/沉积；以及浸润性骨髓源性免疫的募集这些传递的刺激调节驻留脂肪组织巨噬细胞中的内源信号通路。和肝库普弗细胞，并在动脉粥样硬化、肥胖症的巨噬细胞亚群上赋予免疫代谢印记和非酒精性脂肪性肝炎（NASH），这些概念与动脉粥样硬化、肥胖一样具有临床意义。和 NASH 是心血管疾病的既定危险因素。该计划项目将探讨三个因素。具体目标：首先，目标 1（项目 1）将确定热量限制的调节机制巨噬细胞在动脉粥样硬化、肥胖和 NASH 中的器官内和器官间通讯，并确定其影响每个项目正在研究的肝脏免疫细胞中 LXRα 磷酸化对 NASH 相关因素的影响目标 2（项目 2）将探讨 netrin-1 及其受体网络介导巨噬细胞的机制第三，目标 3（项目 3）将探讨动脉粥样硬化、肥胖和 NASH 中的器官内和器官间通讯。 RAGE/DIAPH1 介导巨噬细胞器官内和器官间通讯的机制该计划项目将由三个核心支持：核心 A。（行政，包括生物统计学和生物信息学）；核心B（病理学和生物化学）； C（小鼠育种和程序核心）这个高度积极的项目团队继续致力于协同工作，探究巨噬细胞器官内和器官间的新机制沟通有助于调解和治疗心脏代谢疾病。在人体组织中采用最先进的方法和共享补充检查人类转录组数据库，该计划项目将发现新的机制见解，从而导致消除巨噬细胞过度积累、炎症和炎症的治疗方法放大心血管风险的器官内/间通讯。