In vivo behavior of monocytes in resting and inflammatory conditions

单核细胞在静息和炎症条件下的体内行为

• 批准号: 9416059
• 负责人: Mikael PITTET
• 金额: $ 40.94万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-11-15 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9416059
• 关键词: Address; Adult; Anatomy; Angiotensin II; Arterial Fatty Streak; Atherosclerosis; Behavior; Biology; Bone Marrow; Cell Lineage; Cells; Data; Disease; Disease model; Embryo; Embryonic Development; Exhibits; Extramedullary; FDA approved; Goals; Hematopoietic stem cells; Heterogeneity; Hormones; Image; Immune system; Immunity; Infection; Inflammation; Inflammatory; Injury; Kinetics; Leukocyte Trafficking; Leukocytes; Location; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Mediating; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Pathway interactions; Pharmaceutical Preparations; Phenotype; Positioning Attribute; Process; Production; Reaction; Research; Rest; Site; Source; Spleen; System; TP53 gene; Testing; Therapeutic; Tissues; Work; base; bone; data modeling; disorder control; experience; experimental study; in vivo; macrophage; migration; monocyte; mouse model; mutant; progenitor; public health relevance; response; targeted treatment; trafficking; tumor

 DESCRIPTION (provided by applicant): Macrophages (MØ) are among the immune system's most important defenders of the body by protecting against infection and injury but they also accelerate numerous diseases. Recent studies indicate that many tissue MØ are generated during embryonic development and maintain themselves in adults in the steady-state. In diseased tissues, however, many MØ originate from circulating monocytes (Mo). For example, we found that circulating Mo often infiltrate the ischemic myocardium, atherosclerotic plaques and growing tumors, where they differentiate into MØ and can promote disease. These circulating Mo can be released in large quantities from different reservoir locations, including th bone marrow and spleen, and various diseases enhance Mo production in these reservoirs by amplifying hematopoietic stem and progenitor cells (HSPC) locally. At present, an accurate understanding of disease-induced MØ responses is lacking and requires a more comprehensive analysis of the origins and dynamics of these cells at the organismal level. The research proposed in this application will define both the quantity and quality of tissue MØ based on thei origins. We propose that, in disease, distinct anatomical sites produce different types of MØ precursors and we will thus test the hypothesis that disease-associated tissue MØ responses can be tailored by manipulating these cells' topo-ontogenic sources. First, by taking the entire HSPC➝Mo➝MØ lineage into account we will identify the most important kinetic processes that define the quantity of disease-associated MØ (aim 1). Second, by considering the different origins of these MØ we will uncover maturational pathways that influence their quality in vivo (aim 2). Our findings have therapeutic potential because in both aims we will define how Ang II pathway manipulations control MØ. Ang II is a newly identified driver of HSPC/Mo/MØ-mediated inflammation that is active in a variety of diseases (cancer, atherosclerosis, myocardial infarction) and can be targeted with FDA-approved drugs. Our goal is to develop new advances that can be used to restrain unwanted inflammatory reactions or instead promote delivery of protective immunity to tissue. Our experiments will use the so-called KP tumor mouse model because we have generated data indicating that: i) MØ in KP tumors have a dominant phenotype and promote disease; ii) many of these MØ originate from HSPC and Mo that are produced in bone marrow and spleen; iii) HSPC➝Mo➝MØ lineage amplification in KP mice resembles the one observed in other disease models including myocardial infarction and atherosclerosis; and iv) the hormone Angiotensin (Ang) II amplifies disease-promoting MØ in KP mice. Also, we have assembled a team of experts in imaging, leukocyte trafficking, data modeling and integrative biology to accomplish our goals.

 描述（由申请人提供）：巨噬细胞（MØ）是免疫系统最重要的身体防御者之一，可以防止感染和损伤，但它们也会加速许多疾病的发生。最近的研究表明，许多组织 MØ 是在胚胎发育过程中产生的，并在成人中保持稳定状态。然而，在患病组织中，许多 MØ 源自循环单核细胞 (Mo)。例如，我们发现循环的Mo经常浸润缺血的心肌、动脉粥样硬化斑块和生长的肿瘤，在那里它们分化成MØ并可以促进疾病。这些循环钼可以从不同的储存库位置（包括骨髓和脾脏）大量释放，并且各种疾病通过局部放大造血干细胞和祖细胞（HSPC）来增强这些储存库中钼的产生。目前，缺乏对疾病引起的 MØ 反应的准确理解，需要在有机体水平上对这些细胞的起源和动态进行更全面的分析。本申请中提出的研究将根据组织 MØ 的起源来定义其数量和质量。我们提出，在疾病中，不同的解剖部位会产生不同类型的 MØ 前体，因此我们将检验这样的假设：可以通过操纵这些细胞的拓扑个体源来定制与疾病相关的组织 MØ 反应。首先，通过考虑整个 HSPC➝Mo➝MØ 谱系，我们将确定定义与疾病相关的 MØ 数量的最重要的动力学过程（目标 1）。其次，通过考虑这些 MØ 的不同起源，我们将揭示影响其体内质量的成熟途径（目标 2）。我们的发现具有治疗潜力，因为在这两个目标中，我们将定义 Ang II 通路操作如何控制 MØ。 Ang II 是一种新发现的 HSPC/Mo/MØ 介导的炎症驱动因子，在多种疾病（癌症、动脉粥样硬化、心肌梗塞）中都很活跃，并且可以作为 FDA 批准的药物的靶点。我们的目标是开发新的进展，可用于抑制不必要的炎症反应或促进组织的保护性免疫。我们的实验将使用所谓的 KP 肿瘤小鼠模型，因为我们生成的数据表明： i) KP 肿瘤中的 MØ 具有显性表型并促进疾病； ii) 其中许多 MØ 源自骨髓和脾脏中产生的 HSPC 和 Mo； iii) KP 小鼠中的 HSPC➝Mo➝MØ 谱系扩增类似于在其他疾病模型中观察到的扩增，包括心肌梗死和动脉粥样硬化； iv) 激素血管紧张素 (Ang) II 会放大 KP 小鼠中促进疾病的 MØ。此外，我们还组建了一支由成像、白细胞运输、数据建模和综合生物学领域的专家组成的团队来实现我们的目标。