The Role of the Amino Acid Hypusine in the Maintenance and Function of Tissue-Resident Macrophages

氨基酸马尿苷在组织驻留巨噬细胞的维持和功能中的作用

• 批准号: 10656730
• 负责人: Erika L Pearce
• 金额: $ 53万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656730
• 关键词: Activities of Daily Living; Address; Adult; Alveolar; Amino Acids; Biology; Bone Marrow; Bone Tissue; Cells; Cellular biology; Circulation; Colony-Stimulating Factor Receptors; Data; Development; Disease; Embryo; Enzymes; Fibrosis; GATA6 transcription factor; Gene Expression Profile; Goals; Greater sac of peritoneum; Health; Heart; Hematopoietic; Homeostasis; Human Pathology; Hydroxylation; Immune; Immunity; Kinetics; Knowledge; Life; Lung; Lysine; Macrophage; Maintenance; Malignant Neoplasms; Mediating; Metabolism; Mus; Myocardial Infarction; Organ; Play; Polyamines; Process; Property; Proteins; Publishing; Residencies; Role; Route; Shapes; Signal Transduction; Spermidine; T-Lymphocyte; Testing; Time; Tissues; Transcript; Translations; Tumor Immunity; Tumor-associated macrophages; Work; Yolk Sac; base; comparative; deoxyhypusine; deoxyhypusine monooxygenase; deoxyhypusine synthase; eIF-5A; enzyme substrate; fetal; hypusine; insight; monocyte; pathogen; precursor cell; progenitor; programs; response; self-renewal; translation factor; tumor microenvironment; wound healing

Project Summary Tissue-resident macrophages (TRMs) play fundamental roles in tissue homeostasis, immunity, and disease. Thus, unlocking their biology is key to gaining a deeper knowledge of many human pathologies. TRMs are unique from other hematopoietic cells, most of which are comparatively short-lived and continually replenished from the bone marrow. Instead, TRMs form from yolk sac and fetal progenitors and persist into adult life through self- renewal. Over time, and with kinetics specific to each tissue, these fetal-derived TRMs are replaced in most tissues by bone marrow-derived monocytes, which may subsequently acquire a similar transcriptional profile to their embryonic-derived counterparts. However, our understanding of universal factors that regulate TRMs across tissues is limited. Cellular metabolism is one such factor that governs the differentiation trajectories of various immune cell subsets, but how it shapes TRM differentiation, persistence, and function has yet to be studied in detail. We previously identified polyamine metabolism, and its role in the synthesis of the amino acid hypusine as a central axis governing macrophage metabolism and activation. We also showed that hypusine synthesis directs the ability of T cells to take on distinct effector fates. These findings illuminated hypusine as a focal coordinator of immune cell fate and effector programs. However, how hypusine contributes to tissue immunity and TRM maintenance remains unknown. The sole protein to contain hypusine is the translation factor eIF5A, in which a conserved lysine is enzymatically converted to hypusine in a two-step process via spermidine. Hypusinated eIF5A promotes the translation of transcripts with specific sequence properties. Our goal in this proposal is to gain deep understanding of TRM biology in homeostasis and disease by addressing hypusine metabolism. Our central hypothesis is that hypusine regulates the differentiation of monocyte-derived cells into TRMs and/or their maintenance in tissues, and that by targeting hypusine we can modulate macrophages to benefit disease. We base this on our published work and striking preliminary data suggesting that hypusine synthesis controls macrophage tissue-residency across multiple organs. Our approach will add new insight into how short-lived precursor cells develop into long-lived TRMs that carry out functions essential for life. Importantly, it will establish if hypusine synthesis is a tractable route to modulate TRMs in contexts where they influence disease, such as with tumor-associated macrophages and cancer. We will test our central hypothesis by, 1) investigating the role of hypusine synthesis in TRM formation and/or maintenance, 2) probing the mechanisms through which hypusine governs macrophage tissue-residency, and 3) examining whether manipulating hypusine synthesis in macrophages benefits anti-tumor immunity.

项目概要 组织驻留巨噬细胞（TRM）在组织稳态、免疫和疾病中发挥着重要作用。 因此，了解它们的生物学特性是深入了解许多人类病理学的关键。 TRM 是独一无二的 来自其他造血细胞，其中大多数寿命相对较短，并且不断从造血细胞补充 骨髓。相反，TRM 由卵黄囊和胎儿祖细胞形成，并通过自身的作用持续到成年生活。 更新。随着时间的推移，根据每个组织特有的动力学，这些源自胎儿的 TRM 在大多数组织中都会被取代。 由骨髓来源的单核细胞转化为组织，随后可能获得与 他们的胚胎衍生的对应物。然而，我们对调节 TRM 的普遍因素的理解 跨组织的能力是有限的。细胞代谢是控制细胞分化轨迹的因素之一 各种免疫细胞亚群，但它如何塑造 TRM 分化、持久性和功能仍有待研究 详细研究了。我们之前确定了多胺代谢及其在氨基酸合成中的作用 hypusine 作为控制巨噬细胞代谢和激活的中心轴。我们还表明，下丘脑 合成指导 T 细胞呈现不同效应命运的能力。这些发现表明，前尿嘧啶是一种 免疫细胞命运和效应程序的焦点协调员。然而，前尿嘧啶如何促进组织 免疫力和 TRM 维持仍然未知。唯一含有马尿苷的蛋白质是翻译因子 eIF5A，其中保守的赖氨酸通过亚精胺在两步过程中酶促转化为马尿嘧啶。 Hypusated eIF5A 促进具有特定序列特性的转录本的翻译。我们在这方面的目标 提案旨在通过解决 hypusine 问题来深入了解 TRM 生物学在稳态和疾病中的作用 代谢。我们的中心假设是，hypusine 调节单核细胞衍生的细胞分化为 TRM 和/或它们在组织中的维持，并且通过靶向 hypusine，我们可以调节巨噬细胞 益病。我们基于我们已发表的工作和令人震惊的初步数据表明，hypusine 合成控制巨噬细胞跨多个器官的组织驻留。我们的方法将增加新的见解 短寿命的前体细胞如何发育成长寿命的 TRM，以执行生命必需的功能。重要的是， 它将确定高尿苷合成是否是在 TRM 影响的情况下调节 TRM 的易于处理的途径 疾病，例如与肿瘤相关的巨噬细胞和癌症。我们将通过以下方式检验我们的中心假设：1) 研究高尿苷合成在 TRM 形成和/或维持中的作用，2) 探索机制 hypusine 通过它控制巨噬细胞组织驻留，3) 检查是否操纵 巨噬细胞中的马尿苷合成有利于抗肿瘤免疫。