Macrophages in homeostasis and cardiovascular disease

巨噬细胞在体内平衡和心血管疾病中的作用

• 批准号: 10438328
• 负责人: Filip K Swirski
• 金额: $ 48.56万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-25 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10438328
• 关键词: Adult; Apolipoprotein E; Atherosclerosis; Bacteria; Bone Marrow; Cardiovascular Diseases; Cells; Coupled; Cues; Dangerousness; Development; Diet; Environment; Fetal Liver; Grant; Growth; Home; Homeostasis; IL3 Gene; IL3RA gene; Imaging technology; Immunology; Inflammatory; Ingestion; Ischemia; Knockout Mice; Leukocytes; Ligation; Location; Magnetic Resonance Imaging; Modeling; Molecular Biology Techniques; Myelogenous; Myocardial Infarction; Myocardial Ischemia; Myocardium; Nature; Neurons; Operative Surgical Procedures; Organ; Parabiosis; Phagocytes; Positron-Emission Tomography; Reperfusion Therapy; Shapes; Sleep Fragmentations; Smooth Muscle Myocytes; Source; Spleen; Stimulus; Tissues; Transgenic Mice; Tunica Adventitia; Vascular Smooth Muscle; Yolk Sac; intravital microscopy; macrophage; real-time images; scaffold; spleen transplantation; tool

Macrophages inhabit all major organs. These large phagocytic myeloid leukocytes' primary purpose may be to maintain tissue integrity by ingesting and eliminating dangerous or dispensable material. From clearing bacteria to pruning neurons, macrophages adapt their functions to meet the needs of their home tissues. The recent recognition that tissue macrophages derive from different sources, coupled with the idea that environmental cues and inflammatory stimuli can sculpt and agitate homeostatic order, provides a frame of reference from which we can decipher the breadth and depth of macrophage activity. Here, I will use: (i) models of atherosclerosis (Ldlr–/–, Apoe–/–, PCSK9-Ad) and myocardial infarction (permanent ligation, ischemia reperfusion); (ii) environmental stimuli (diet, sleep fragmentation); (iii) transgenic and knockout mice (Cx3cr1CreERT2 R26-tdT, IL-3–/–, Csf2–/–, Csf2rb–/–, CD123–/–); (iv) surgical procedures (parabiosis, spleen transplantation); (v) real-time imaging technologies (PET-MRI, intravital microscopy); and (vi) many immunology and molecular biology techniques to investigate macrophage development and function in cardiovascular disease. In aggregate, these tools will allow to decipher how macrophages of different orgins (yolk sac, fetal liver, adult bone marrow, adult spleen, vascular smooth muscle cells) and in different locations (adventitia, intima, ischemic myocardium, remote myocardium) collaborate with and differ from one another during atherosclerosis and its complications. A central concept of this grant is the tension between macrophage ontogeny as a determinant of macrophage function and the idea that tissues condition macrophage activities and supplant the influence of macrophage ontogeny in favor of environmental demands.

巨噬细胞居住在所有主要器官中。这些大吞噬细胞髓白细胞的主要目的可能是 通过摄入并消除危险或可支配物质来维持组织完整性。从清理 细菌可修剪神经元，巨噬细胞适应其功能以满足其家庭组织的需求。 最近认识到组织巨噬细胞来自不同来源，再加上这样的想法 环境提示和炎症刺激可以雕刻和搅动稳态秩序，提供了一个框架 我们可以从中解释巨噬细胞活性的广度和深度。在这里，我将使用：（i） 动脉粥样硬化模型（LDLR - / - ，APOE - / - ，PCSK9-AD）和心肌梗塞（永久连接，缺血 再灌注）; （ii）环境刺激（饮食，睡眠破碎）； （iii）转基因和淘汰小鼠 （CX3CR1CREERT2 R26-TDT，IL-3 - / - ，CSF2 - / - ，CSF2RB - / - ，CD123 - / - ）; （iv）外科手术（抛物线，索伦 移植）； （v）实时成像技术（PET-MRI，浸润显微镜）； （vi）许多 免疫学和分子生物学技术，用于研究巨噬细胞的发展和功能 心血管疾病。总体而言，这些工具将允许解读不同Orgin的巨噬细胞 （蛋黄囊，胎儿肝，成年骨髓，成年作为，血管平滑肌细胞）和不同位置 （Adventitia，Intima，缺血性心肌，远程心肌）与彼此合作并与众不同 在动脉粥样硬化及其并发症期间。这笔赠款的一个核心概念是巨噬细胞之间的张力 个体发育作为巨噬细胞功能的决定因素，以及组织调节巨噬细胞活性的想法 并取代了巨噬细胞的影响，而有利于环境需求。