Transcriptional basis of embryonic macrophage development

胚胎巨噬细胞发育的转录基础

• 批准号: 10531441
• 负责人: Kenneth M Murphy
• 金额: $ 19.69万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10531441
• 关键词: ATAC-seq; Ablation; Adult; Amyloid; Area; Binding; Biological Models; Birth; Bone Marrow; Brain; CRISPR/Cas technology; Cells; Data; Defect; Dendritic Cells; Development; Embryo; Embryonic Development; Enhancers; Evaluation; Extracellular Protein; Fetal Development; Fetal Liver; Gene Expression; Genes; Genetic; Genetic Transcription; Heart; Hematopoiesis; Homeostasis; Immune; Immunity; Knowledge; Kupffer Cells; Life; Liver; Lung; Methods; Microglia; Modeling; Molecular; Mus; Mutation; Myeloid Cells; Neuraxis; Pathway interactions; Play; Population; Process; Proteins; Publications; Publishing; Reporter; Risk; Role; Site; Skin; Supporting Cell; System; Testing; Thalassemia; Tissues; Work; Yolk Sac; base; blastomere structure; brain tissue; fetal; in vivo; macrophage; model design; monocyte; novel; prevent; progenitor; programs; repaired; stem; success; tau Proteins; transcription factor; virtual

ABSTRACT It has been appreciated recently that tissue-resident macrophages (TRMs) contribute to tissue homeostasis. For example, in the brain, microglia have been proposed to process extracellular proteins and to restrict the formation of plaque formed from proteins such as -amyloid and Tau proteins. Such tissue-resident macro- phages were once thought to be derived from monocytes that arise in definitive hematopoiesis in the adult bone marrow. However, we now understand that TRMs are derived during fetal life and arise from progenitors in the yolk sac and fetal liver. In some tissues, these embryonically derived macrophage populations persist throughout adult life and are not efficiently replaced by circulating monocytes arising from adult bone marrow and definitive hematopoiesis. One impediment to studying the functions of such embryonically derived macro- phages is the relative paucity of information regarding their development, specifically the transcriptional pro- grams that guide their development. The lack of such information prevents the design of model systems where these cells can be prevented from developing, which would allow their in vivo functions to be defined in a defin- itive way. The current application is aimed at defining the basis for the embryonic development of macrophag- es. It is based on preliminary data that has: 1) identified the Zeb2 enhancer (at -165kb) used in definitive hematopoiesis supporting monocyte/macrophage development from the adult bone marrow; 2) showed that this enhancer is not required for Zeb2 expression in embryonic macrophage development, and 3) identified two other Zeb2 enhancers that are selectively active in the embryonic yolk sac and fetal liver progenitors. This application will (Aim 1) test these embryonically active Zeb2 enhancers for their role in supporting embry- onic macrophage development, and (Aim 2) determine the transcriptional basis for their embryonic activity. Aim 1 may directly produce models of embryonic macrophage deficiency, which would immediately benefit re- search in other areas related to immune cell support of tissue homeostasis. Beyond this, the basic information on the similarities or differences between primitive and adult hematopoiesis could have further uses, such as in adding to ways in which fetal gene expression can be controlled to compensate for innate or acquired defects in adult gene expression, such as in -thalassemia.

抽象的 最近人们对组织居民巨噬细胞（TRM）有助于组织稳态。 例如，在大脑中，已经提出了小胶质细胞来处理细胞外蛋白质并限制 由蛋白（例如淀粉样蛋白和tau蛋白）形成的斑块形成。这样的组织居民宏观 曾经认为噬菌体源自成人造血的单核细胞 骨髓。但是，我们现在了解到TRM是在胎儿生活中得出的，并且来自祖细胞 在某些组织中，这些胚胎衍生的巨噬细胞种群持续存在 在整个成人生活中，不被成年骨髓引起的循环单核细胞有效地取代 和确定的造血。研究这种胚胎衍生的宏的功能的一种障碍 噬菌体是相对缺乏有关其发展的信息，特别是转录副本 指导他们发展的克。缺乏此类信息阻止了模型系统的设计 可以防止这些细胞发育，这将使它们的体内函数在定义中定义 - IDIVE方法。当前的应用旨在定义巨噬菌的胚胎发展的基础。 es。它基于具有：1）确定Zeb2增强子（AT -165KB）的初步数据 由成年骨髓支撑单核细胞/巨噬细胞发育的造血症； 2）显示 在胚胎巨噬细胞发展中Zeb2表达不需要此增强子，3）确定了两个 其他在胚胎蛋黄和胎儿肝祖细胞中有选择性活跃的Zeb2增强剂。 该应用将（AIM 1）测试这些具有胚胎活跃的Zeb2增强子，以在支持胚胎中的作用 ONIC巨噬细胞的发展，（目标2）确定其胚胎活性的转录基础。 AIM 1可能直接产生胚胎巨噬细胞缺乏症的模型，这将立即受益 在与组织稳态支持的其他领域进行搜索。除此之外，基本信息 关于原始造血和成人造血之间的相似性或差异，例如 增加可以控制胎儿基因表达以补偿先天或获得的缺陷的方式 在成年基因表达中，例如在thalassymia中。