Regulation of tissue resident macrophage development by IL-7R signaling

IL-7R 信号传导调节组织驻留巨噬细胞发育

• 批准号: 10303707
• 负责人: Anna E. Beaudin
• 金额: $ 34.31万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303707
• 关键词: Activities of Daily Living; Address; Adoptive Transfer; Adult; Automobile Driving; Blood; Cell physiology; Cells; Characteristics; Cues; Cytokine Receptors; Data; Development; Developmental Process; Disease; Epidermis; Fetal Development; Fetal Liver; Fetal Tissues; Genetic Transcription; Goals; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Homeostasis; IL7 gene; IL7R gene; Immune; Immunity; Immunologic Surveillance; Impairment; Interleukin 7 Receptor; Investigation; Knowledge; Label; Longevity; Lung; Lymphocyte; Lymphoid; Maintenance; Molecular; Mus; Myelogenous; Myeloid Cells; Natural regeneration; Nature; Normal tissue morphology; Pathogenesis; Pathway interactions; Pregnancy; Process; Production; Property; Receptor Signaling; Recording of previous events; Regulation; Research Project Grants; Role; Shapes; Signal Pathway; Signal Transduction; Specific qualifier value; Surface; Time; Tissues; Transducers; Work; brain tissue; experimental study; fetal; genetic approach; immune function; insight; macrophage; monocyte; novel; progenitor; protein expression; receptor; self-renewal

The recent discovery that adult hematopoietic (blood) stem cells (HSCs) do not produce all immune cells despite sustaining blood production across the lifespan has fundamentally challenged our understanding of both immune development and function. Adoptive transfer studies and fate mapping experiments have demonstrated that tissue-resident macrophages are only specified during fetal development and cannot be generated or regenerated in adulthood. As compared to their adult HSC-derived counterparts, fetal-derived tissue resident macrophages reside and self-renew within their resident tissues, where they perform distinct homeostatic and immune surveillance functions. The discovery of a fetal origin of tissue-resident macrophages has raised many new questions about their specification, persistence across the lifespan, and distinct function. The long-term objective of this proposal is to define the developmental mechanisms underlying the unique functional capacity of tissue resident macrophages across the lifespan in order to illuminate their distinct role in both adult tissue homeostasis and disease. Recent work in our lab has identified interleukin-7 receptor (IL-7R) signaling as a novel mechanism regulating the establishment of tissue resident macrophages during fetal development. IL-7R signaling is restricted to regulation of the lymphoid lineage in adult hematopoiesis. The reliance of fetal myeloid specification on IL-7R signaling suggests that fetal hematopoiesis exploits alternate differentiation pathways in order to confer distinct characteristics on fetal-derived macrophages. In this proposal, we will capitalize on the discovery of this new regulatory mechanism to dig deeper into how these distinct immune cells are specified from fetal precursors during development. In Aim 1, we will use genetic approaches to determine the requirement for IL7R signaling during fetal myeloid specification. We will specifically delete the receptor sub-chain IL7raain a range of progenitors and mature cells at different stages of development to define how IL7rα regulates myeloid specification during fetal development. In Aim 2, we will define for the first time how IL-7R signaling occurs in myeloid cells - including downstream signal transducers and transcriptional targets- and the specific developmental processes that are regulated by IL-7R signaling during fetal macrophage establishment. In Aim 3, we will establish the function of IL-7 as a fetal myeloid niche factor and define both the requirement for IL-7 and which cell subsets are responsible for producing IL-7 within resident tissues to support macrophage development. Together, work from the proposed studies will illuminate how alternative differentiation pathways during fetal hematopoiesis impart distinct functional characteristics on fetal-derived tissue resident macrophages, and thereby illuminate the role of specific ontogenetic subsets of macrophages in normal tissue and disease processes.

最近发现成年造血（血液）干细胞（HSC）的发现并未产生所有免疫细胞 尽管在整个生命周期中维持了血液产量，但从根本上挑战了我们对 免疫发育和功能。收养转移研究和脂肪映射实验具有 证明组织居民巨噬细胞仅在胎儿发育过程中指定，不能是 成年后产生或再生。与成人HSC衍生的同行相比，胎儿衍生 组织居民巨噬细胞居住在其居民时机内，在那里进行独特 稳态和免疫监视功能。发现组织 - 居民巨噬细胞的胎儿起源 已经提出了许多有关其规格，整个寿命的持久性以及独特功能的新问题。 该提议的长期目标是定义独特的发展机制 组织居民在整个生命周期中巨噬细胞的功能能力，以阐明其在 成人组织稳态和疾病。我们实验室的最新工作已经确定了白介素-7受体（IL-7R） 信号传导是一种新的机制，该机制是胎儿期间组织居民巨噬细胞的建立 发展。 IL-7R信号传导仅限于成年造血症中淋巴样谱系的调节。 对IL-7R信号传导的胎儿髓样规范的依赖表明胎儿造血利用替代 分化途径以赋予胎儿来源的巨噬细胞的不同特征。在这个 提案，我们将利用这种新的监管机制的发现，以深入研究这些机制 在发育过程中指定了不同的免疫细胞。在AIM 1中，我们将使用通用 在胎儿髓样规范期间确定IL7R信号传导需求的方法。我们将 明确删除接收器子链IL7AAIN在不同阶段的祖细胞和成熟细胞的范围 定义IL7Rα在胎儿发育过程中如何调节髓样规范的开发。在AIM 2中，我们将 首次定义IL -7R信号在髓样细胞中的发生 - 包括下游信号传感器 以及由IL-7R信号调节的转录目标和特定的发育过程 在胎儿巨噬细胞建立期间。在AIM 3中，我们将确定IL-7作为胎儿髓样生态位的功能 因子并定义了IL-7的需求，以及哪些细胞子集负责在内部产生IL-7 居民组织支持巨噬细胞的发展。拟议研究的工作一起阐明 胎儿造血期间的替代分化途径如何在上赋予不同的功能特征 胎儿衍生的组织居民巨噬细胞，从而阐明 正常组织和疾病过程中的巨噬细胞。