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

• 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
• 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

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、储存和线索依赖性的关键作用 心脏代谢功能障碍中的分子重新编程 ANTRAORGAN 通讯。 团队将在这些发现的基础上开拓新的方向。 通信，并通过器官间通信、巨噬细胞和其他生物活性介质的家园。 渗透不同部位，例如肥胖脂肪组织中的硬化斑块； 在心脏代谢功能障碍中，肝脏是重新增加的内毒素。 来自肠道的脂肪组织中的脂质积累；以及增加损伤相关的生物利用度 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 病理性脂质的过量合成/沉积；以及浸润性骨髓源性免疫的募集 细胞。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传导通路。 肝库普弗细胞和动脉粥样硬化巨噬细胞亚群的免疫代谢印记。 Andn-酒精性脂肪性肝炎 (NASH) 这些概念具有临床意义、动脉粥样硬化、肥胖。 纳什建立了心血管疾病的危险因素“探索三三三”。 具体目标：首先，目标 1（项目 1）将确定热量限制媒介的机制 动脉粥样硬化、肥胖和纳什中的巨噬细胞内和器官间通讯，并定义其影响 每个项目都在研究肝脏免疫细胞中 lxrα 磷酸化对纳什相关因素的影响。 AIM 2（项目2）将探讨Netrin-1和受体网络MediaTe巨噬细胞的机制 动脉粥样硬化、肥胖和纳什中的安器官内通讯 第三，目标 3（项目 3）WiLL PROBE。 RAGE/DIAPH1 介导巨噬细胞内和器官间通讯的机制 动脉粥样硬化、肥胖和纳什计划项目将由三个核心支持：核心 A 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核心）集体地，这个高度积极的计划项目团队继续进行。 协同合作探索巨噬细胞器官内和器官间的新机制 通信有助于心脏代谢疾病的媒体和治疗。 在人体组织中采用最新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 Mecover 见解，从而导致 抑制巨噬细胞过度积累、炎症和炎症的治疗方法 放大心血管风险的器官内/器官间通讯。