Macrophage development and specification in mice.

小鼠巨噬细胞的发育和规范。

• 批准号: 10153684
• 负责人: Frederic Geissmann
• 金额: $ 60.41万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-08 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153684
• 关键词: Adult; Alveolar Macrophages; Anatomy; Antigen-Presenting Cells; Blood Vessels; Bone Marrow; Bone Marrow Transplantation; Brain; Cell Differentiation process; Cells; Clinical; Complex; Cues; Degenerative Disorder; Development; Developmental Process; Disease; Embryo; Embryonic Development; Enhancers; Epithelial; Erythro; Event; Family; Fetal Development; Filopodia; Genetic; Genetic Polymorphism; Genetic Transcription; Genomics; Glycoproteins; Goals; Growth; Growth Factor; Health; Hematopoietic stem cells; Homeostasis; Immune; In Situ; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Investigation; Kidney; Kupffer Cells; Label; Laboratories; Lamina Propria; Langerhans cell; Lipids; Literature; Liver; Lung; Maintenance; Methods; Microglia; Modeling; Molecular; Mononuclear; Morphogenesis; Mus; Myelogenous; Myeloid Cells; Natural Immunity; Neurophysiology - biologic function; Organ; Organogenesis; Pathogenesis; Pattern; Phagocytes; Phenotype; Play; Population; Process; Regulation; Research; Role; Sentinel; Specific qualifier value; Supporting Cell; System; Systems Biology; Testing; Tissue Differentiation; Tissues; Work; Yolk Sac; antimicrobial; brain cell; cell motility; cell type; epidermis cell; expectation; global health; in vivo; insight; irradiation; lymphatic vessel; macrophage; member; monocyte; neurogenesis; novel; pathogen; postnatal; progenitor; programs; recruit; repaired; spatiotemporal; tissue repair; tool; transcription factor; transcriptome sequencing; transplant model; tumor; uptake

Project Summary Macrophages are a diverse family of professional phagocytes and `accessory cells' present within most tissues, and equipped with long and motile filopodia that continuously explore surrounding matrix and cells. Macrophages recognize and scavenge pathogens as well as unfit cells and cell debris, glycoproteins and lipids, and produce a large range of bioactive molecules and growth factors. A literature that covers 150 years of research has demonstrated their important and complex roles (i) as innate immune sentinels for the uptake of pathogens, but also as (ii) regulators of epithelia and blood and lymphatic vessels morphogenesis during fetal development, postnatal homeostasis and tissue remodeling, and inflammatory and degenerative processes. An overarching hypothesis that drives the present proposal and the work of our laboratory is that the understanding the genetic and molecular events that control development, growth, and maintenance of macrophages within tissues is essential to elucidate their roles in disease and the consequence(s) of genetic polymorphisms. Early studies suggested that tissue macrophages originate and renew from hematopoietic stem cells (HSC) via circulating progenitors such as blood monocytes. However, as recently shown by us and others, monocytes and macrophages play different roles in disease pathogenesis, and in fact, they represent distinct cell types, as most tissue-resident macrophages develop from embryonic progenitors distinct from HSCs and are maintained in postnatal tissues independently of bone marrow progenitors and monocytes. Furthermore, macrophages that reside in distinct tissues present with different molecular identities and functions. The tissue-specific identities of macrophages are in part maintained by their local microenvironment, but are also likely to result from developmental processes. The present project builds on these exciting and `paradigm-changing' developments. 1) We will characterize the genetic and molecular determinants that control macrophage development from embryonic progenitors in the mouse, using sate-of-the-art fate mapping methods, and explore the mechanisms that underlie the colonization of embryos by the macrophages precursors. 2) We will also take advantage of single-cell genomic and systems biology approaches to characterize the mechanisms and spatio-temporal sequence of events responsible for tissue macrophage specification in vivo. We will further test the role of novel key transcriptional regulators that control macrophage differentiation, maintenance, and functions in postnatal tissues, with a focus on Kupffer cells. Along this process we will generate novel genetic tools needed to distinguish and selectively target tissue-resident macrophages, independently of HSC and their progeny. Altogether, this work represents a ground-breaking advance toward our aim to characterize the function of tissue-resident macrophage in health and disease.

项目摘要 巨噬细胞是存在于大多数细胞中的专职吞噬细胞和“辅助细胞”的多样化家族。 组织，并配备长而能动的丝状伪足，不断探索周围的基质和细胞。 巨噬细胞识别并清除病原体以及不适合的细胞和细胞碎片、糖蛋白和 脂质，并产生大范围的生物活性分子和生长因子。 一项涵盖150年研究的文献表明，它们具有重要而复杂的作用：（i）与生俱来的 用于病原体摄取的免疫哨兵，但也作为（ii）上皮细胞和血液及淋巴的调节剂 胎儿发育期间的血管形态发生、出生后的体内平衡和组织重塑，以及 炎症和退化过程。驱动本提案的总体假设和 我们实验室的工作是了解控制发育的遗传和分子事件， 巨噬细胞在组织内的生长和维持对于阐明它们在疾病中的作用是必不可少的， 遗传多态性的后果。 早期的研究表明，组织巨噬细胞起源于造血干细胞（HSC），并通过 循环祖细胞，例如血液单核细胞。然而，正如我们和其他人最近所示，单核细胞 和巨噬细胞在疾病发病机制中发挥不同的作用，事实上，它们代表不同的细胞类型， 大多数组织驻留巨噬细胞从不同于HSC的胚胎祖细胞发育而来， 在出生后的组织中独立于骨髓祖细胞和单核细胞。此外，巨噬细胞 它们存在于不同的组织中，具有不同的分子身份和功能。组织特异 巨噬细胞的特性部分由其局部微环境维持，但也可能导致 来自发展过程。 本项目以这些令人兴奋的“改变范式”的发展为基础。1)我们将描述 控制巨噬细胞从胚胎祖细胞发育的遗传和分子决定因素， 小鼠，使用最先进的命运映射方法，并探索其背后的机制， 巨噬细胞前体对胚胎的定植。2)我们还将利用单细胞基因组 和系统生物学的方法来表征的机制和时空序列的事件 负责体内组织巨噬细胞的特化。我们将进一步测试新的关键转录因子的作用， 在出生后组织中控制巨噬细胞分化、维持和功能的调节剂， 专注于枯否细胞沿着这一过程，我们将产生新的遗传工具， 选择性靶向组织驻留巨噬细胞，独立于HSC及其后代。总之，这项工作 代表了我们的目标是表征组织驻留功能的突破性进展， 巨噬细胞在健康和疾病。