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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：
10616525
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/10616525
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 Cytoplasm Databases Deposition Diabetes Mellitus Employment Endotoxins Fostering Functional disorder Funding High Fat Diet Home Human Immune Immune response Infiltration Inflammation Inflammatory Insulin Resistance Kupffer Cells LXRalpha protein Lipids Liver Macrophage Mediating Mediation Mediator Metabolic Metabolic dysfunction Metabolism Molecular Mus Myelogenous NTN1 gene Nervous System Obesity Organ Pathologic Pathology Patients Pattern Phosphorylation Play Procedures Process Program Research Project Grants Regulation Resolution Shapes Signal Pathway Site Stimulus Therapeutic Thermogenesis Tissues Work atherosclerosis risk cardiometabolism cardiovascular disorder risk cardiovascular risk factor clinically significant comorbidity experience forging human tissue imprint in vivo inhibitor insight 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.

摘要：总体这项计划项目拨款揭示了巨噬细胞新陈代谢的关键作用，依赖于库和线索心脏代谢性功能障碍中的分子重编程和器官内通讯。计划项目团队将在这些发现的基础上再接再厉，开拓新的方向。巨噬细胞在器官内的调节作用通过器官间通讯，巨噬细胞和其他生物活性介质并渗入不同的部位，如在动脉粥样硬化斑块中；在肥胖的脂肪组织中；以及新的在这个循环中探索的；在肝脏中。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的；脂肪组织中脂肪的积累；以及与损伤相关的生物利用度的提高分子模式。在每个新陈代谢器官中，组织特有的生态位定义了无数的后果，如由于病理性脂质的过度合成/沉积；以及募集浸润性骨髓源性免疫细胞。这些递送的刺激调节常驻脂肪组织巨噬细胞的内源性信号通路和肝Kupffer细胞及巨噬细胞亚群在动脉粥样硬化、肥胖中的免疫代谢印记和非酒精性脂肪性肝炎(NASH)。这些概念具有临床意义，如动脉粥样硬化、肥胖和NASH是心血管疾病的既定危险因素。该计划项目将探索三个具体目标：首先，目标1(项目1)将确定卡路里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 LXRα在肝脏免疫细胞中的磷酸化对NASH相关因子的影响正在每个项目中研究。第二, 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动脉粥样硬化、肥胖和NASH中的器官内和器官间通讯。第三，目标3(项目3)将探索 RAGE/DIAPH1介导巨噬细胞器官内和器官间通讯的机制动脉粥样硬化、肥胖和NASH。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)；以及核心 C(老鼠培育和程序核心)。总体而言，这个充满干劲的计划项目团队继续协同工作以询问巨噬细胞器官内和器官间的新机制传播有助于心脏代谢性疾病的调解和补救。通过使用最先进的方法和共享互补检查在人体组织和人类转录组数据库，该计划项目将发现新的机械性见解，从而导致治疗方法，以消除夸大的巨噬细胞聚集，炎症和放大心血管风险的器官内/器官间通讯。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Diabetes and Metabolic Drivers of Trained Immunity: New Therapeutic Targets Beyond Glucose.

培训免疫的糖尿病和代谢驱动因素：葡萄糖以外的新治疗靶标。

DOI：
10.1161/atvbaha.120.314211
发表时间：
2021-04
期刊：
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
影响因子：
8.7
作者：
Choudhury, Robin P.;Edgar, Laurienne;Ryden, Mikael;Fisher, Edward A.
通讯作者：
Fisher, Edward A.

The receptor for advanced glycation end products (RAGE) and DIAPH1: unique mechanisms and healing the wounded vascular system.

晚期糖基化终末产物 (RAGE) 和 DIAPH1 的受体：独特的机制和治愈受伤的血管系统。

DOI：
10.1080/14789450.2018.1536551
发表时间：
2019
期刊：
Expert review of proteomics
影响因子：
3.4
作者：
Ramasamy,Ravichandran;Friedman,RichardA;Shekhtman,Alexander;Schmidt,AnnMarie
通讯作者：
Schmidt,AnnMarie

Obesity research: Moving from bench to bedside to population.