Development of the resident macrophage lineage in mouse and human

小鼠和人类常驻巨噬细胞谱系的发展

• 批准号: 10660034
• 负责人: Frederic Geissmann
• 金额: $ 71.44万
• 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 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660034
• 关键词: Address; Animal Model; Brain; Cell Lineage; Development; Disease; Embryo; Embryonic Development; Energy Metabolism; Erythro; Event; Face; Fatty acid glycerol esters; Funding; Genetic; Goals; Hematopoiesis; Hematopoietic stem cells; Homeostasis; Human; Impairment; Individual; Inflammatory; Investigation; Legal patent; Leukocytes; Lipids; Macrophage; Maintenance; Maps; Modeling; Molecular; Mus; Mutation; Myelogenous; Nature; Neurodegenerative Disorders; Organ; Organogenesis; Osteoclasts; Outcome; Pathogenesis; Patients; Phenotype; Physiology; Population; Progress Reports; Publications; Reporting; Resolution; Role; Science; Specific qualifier value; Supporting Cell; Therapeutic; Time; Tissues; Vertebrates; Work; Yolk Sac; Zebrafish; acquired factor; bone; gastrulation; hematopoietic differentiation; improved; in vitro Model; in vivo; induced pluripotent stem cell; insight; mouse model; mutant; novel; novel therapeutic intervention; pharmacologic; postnatal; progenitor; programs; repaired; tool; transcription factor; tumor

Title: Development of the resident macrophage lineage in mouse and human Summary/abstract Our long-range goal in our previous funded RO1 application was to elucidate mechanisms that underlie the development and specification of embryo-derived tissue-resident macrophages in mice. Our program of work aimed to understand how the identities and functions of resident macrophages are specified and to provide tools and concepts to identify pathophysiological mechanisms underlying their roles in developmental, inflammatory, degenerative and tumoral diseases. This work allowed us to identify key novel functions of resident macrophages and mechanisms that underly these functions and to develop new genetically tractable models which pave the way for our current project. Yet, a comprehensive understanding of the developmental origin and functions of mammalian resident macrophages, which has essential implications for genetic and pharmacological investigations of their specialized functions, still faces several important challenges, which are identified and addressed in this renewal proposal. 1) The development of resident macrophage in mice cannot be directly extrapolated to humans because the earlier steps of extraembryonic hematopoiesis and macrophage development present with differences among vertebrates, for example between Zebrafish and mice, and are overall poorly understood. Notably, 2) the early hemato-endothelial progenitor(s) that give rise to EMPs and HSCs are still elusive, which impairs our ability to fully characterize resident macrophages. In addition, 3) it is important to elucidate the roles of individual LDTFs and their subset-specific combinations for the control of tissue-specific functions of macrophages, because, in addition to identify molecular mechanisms that underly macrophage functions, these studies have the potential to unveil therapeutic strategies for leveraging macrophage functions in human. We propose to take advantage of novel genetic tools to identify the hemato- endothelial progenitors that generate the macrophage lineage in mice (AIM1), to identify conserved macrophages progenitors in human using a genetically tractable model for hematopoietic differentiation in human induced pluripotent stem cell (hiPSC)-derived embryoid bodies, and to take advantage of this versatile in vitro model to characterize the role of macrophage LDTFs in the control of macrophage tissue-specific functions (AIM2). We expect that our results will provide a robust experimental basis to transform and improve our understanding of the cellular, genetic, and molecular determinants of resident-macrophage development in mice and, importantly, in human, and provide important genetic tools for the molecular understanding and manipulation of their functions in physiology and diseases.

标题： 小鼠和人类常驻巨噬细胞谱系的发育 摘要/摘要 我们之前资助的 RO1 申请中的长期目标是阐明潜在的机制 小鼠胚胎来源的组织驻留巨噬细胞的发育和规范。我们的工作计划 旨在了解驻留巨噬细胞的身份和功能是如何确定的并提供工具 和概念来确定其在发育、炎症、 退行性疾病和肿瘤疾病。这项工作使我们能够确定常驻巨噬细胞的关键新功能 以及这些功能背后的机制，并开发新的遗传易处理模型，为 我们当前项目的方式。然而，对发育起源和功能的全面了解 哺乳动物常驻巨噬细胞，这对遗传和药理学具有重要意义 对它们的专门职能的调查，仍然面临着几个重要的挑战，这些挑战已确定 并在本更新提案中得到解决。 1）小鼠常驻巨噬细胞的发育不能 直接外推到人类，因为胚胎外造血和巨噬细胞的早期步骤 脊椎动物之间的发育存在差异，例如斑马鱼和小鼠之间，并且 总体了解甚少。值得注意的是，2) 产生 EMP 的早期血内皮祖细胞和 HSC 仍然难以捉摸，这削弱了我们充分表征驻留巨噬细胞的能力。另外，3) 是 阐明各个 LDTF 及其子集特定组合在控制 巨噬细胞的组织特异性功能，因为除了确定其背后的分子机制外， 巨噬细胞功能，这些研究有可能揭示利用巨噬细胞功能的治疗策略 巨噬细胞在人体中发挥作用。我们建议利用新型遗传工具来识别血液 产生小鼠巨噬细胞谱系的内皮祖细胞 (AIM1)，以鉴定保守的 使用人类造血分化的遗传易处理模型来研究人类巨噬细胞祖细胞 诱导多能干细胞（hiPSC）衍生的胚状体，并利用这种多功能的体外 表征巨噬细胞 LDTF 在控制巨噬细胞组织特异性功能中的作用的模型 （目标2）。我们期望我们的结果将为改造和改进我们的研究提供坚实的实验基础 了解小鼠常驻巨噬细胞发育的细胞、遗传和分子决定因素 重要的是，在人类中，并为分子理解和 操纵它们在生理和疾病中的功能。