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：总体该计划项目赠款已揭示了巨噬细胞代谢，仓库和提示依赖性的关键作用心脏代谢功能障碍中的分子重新编程和内部通信。程序项目团队将基于这些发现并为新的方向发展。巨噬细胞媒体内部通信以及通过跨组织通讯，巨噬细胞和其他生物活性调解人的家和浸润不同的位点，例如在动脉粥样硬化斑块中；在肥胖的脂肪组织中；并新在这个周期中探索；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从肠道脂肪组织中脂质的积累；并增加了与损害相关的生物利用度分子模式。在每个代谢器官中，组织特异性的利基市场定义了无数的后果超过病理脂质的合成/沉积；并募集浸润的骨髓衍生的免疫细胞。这些传递的刺激调节居民脂肪组织巨噬细胞中的内源信号通路和肝库普弗细胞以及动脉粥样硬化中巨噬细胞子集的免疫代谢烙印，肥胖症和非酒精性脂肪性肝炎（NASH）。这些概念在临床上很重要，作为动脉粥样硬化，肥胖症纳什（Nash）是心血管疾病的确定风险因素。该计划项目将探索三个具体目的：首先，AIM 1（项目1）将确定热量限制的机制动脉粥样硬化，肥胖和纳什的巨噬细胞内和跨组织通信，并定义了影响在每个项目中研究的NASH相关因素上，肝脏免疫细胞中LXRα磷酸化的磷酸化。第二， AIM 2（项目2）将探测Netrin-1及其接收器网络介导巨噬细胞的机制动脉粥样硬化，肥胖症和纳什（Nash）中的组织内和组织内通信。第三，AIM 3（项目3）将证明愤怒/diaph1介导巨噬细胞内部和跨组织内部通信的机制动脉粥样硬化，肥胖和纳什。该计划项目将由三个内核支持：核心A （行政，包括生物统计学和生物信息学）；核B（病理和生物化学）；和核心 C（小鼠育种和过程核心）。总的来说，这个高度动机的计划项目团队继续通过协同质疑巨噬细胞内部和跨组织的新机制协同作用通信有助于心脏代谢疾病的调解和修复。通过在人体组织中使用最先进的方法和共享的完善考试人类转录组数据库，该程序项目将发现导致的新机械见解治疗方法来消除夸张的巨噬细胞积累，炎症和扩大心血管风险的内部/跨组织内部通信。

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.

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.