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: 9242734
• 负责人: Filip K Swirski
• 金额: $ 42.75万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9242734
• 关键词: Adult; Apolipoprotein E; Atherosclerosis; Bacteria; Bone Marrow; Cardiovascular Diseases; Cells; Coupled; Cues; Dangerousness; Development; Diet; Environment; Fetal Liver; Grant; Growth; Home environment; Homeostasis; IL3RA gene; Imaging technology; Immunology; Inflammatory; Interleukin-3; Ischemia; Knockout Mice; Leukocytes; Ligation; Location; Magnetic Resonance Imaging; Modeling; Molecular Biology Techniques; Muscle Cells; Myelogenous; Myocardial Infarction; Myocardial Ischemia; Myocardium; Nature; Neurons; Operative Surgical Procedures; Organ; Parabiosis; Phagocytes; Positron-Emission Tomography; Reperfusion Therapy; Shapes; Sleep Fragmentations; Source; Spleen; Stimulus; Time; Tissues; Transgenic Mice; Tunica Adventitia; Vascular Smooth Muscle; Yolk Sac; intravital microscopy; macrophage; 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.

巨噬细胞存在于所有主要器官中。这些大型吞噬性髓系白细胞的主要目的可能是： 通过摄入和消除危险或可有可无的物质来保持组织完整性。 从细菌到修剪神经元，巨噬细胞调整其功能以满足其自身组织的需求。 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 环境线索和炎症刺激可以塑造和扰乱体内平衡秩序，提供一个框架 我们可以从中解读巨噬细胞活动的广度和深度，在这里，我将使用：（i）。 动脉粥样硬化模型（Ldlr–/–、Apoe–/–、PCSK9-Ad）和心肌梗塞模型（永久结扎、缺血 (ii) 环境刺激（饮食、睡眠碎片化）； (iii) 转基因和基因敲除小鼠； (Cx3cr1CreERT2 R26-tdT、IL-3–/–、Csf2–/–、Csf2rb–/–、CD123–/–)；(iv) 外科手术（联体共生、脾脏） (v) 实时成像技术（PET-MRI、活体显微镜）；以及 (vi) 许多技术 免疫学和分子生物学技术研究巨噬细胞的发育和功能 总的来说，这些工具将有助于破译不同来源的巨噬细胞的作用。 （卵黄囊、胎儿肝脏、成人骨髓、成人脾脏、血管平滑肌细胞）和不同位置 （外膜、内膜、缺血性心肌、远端心肌）相互协作又各不相同 动脉粥样硬化及其并发症期间的一个核心概念是巨噬细胞之间的紧张关系。 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动的想法 并取代巨噬细胞个体发育的影响以适应环境需求。