Macrophage Dysfunction in Atherosclerosis and Cardiometabolic Diseases

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。

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.