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.

项目摘要 组织居民巨噬细胞（TRM）在组织稳态，免疫和疾病中起着基本作用。 因此，解锁生物学是对许多人类病理学的更深入了解的关键。 TRM是独一无二的 来自其他造血细胞，其中大多数是相对短暂的，并不断地从 骨髓。取而代 更新。随着时间的流逝，对于每种组织的动力学，这些胎儿衍生的TRM大多都被替换 通过骨髓衍生的单核细胞组织，随后可能获得与 他们的胚胎衍生的对应物。但是，我们对调节TRM的普遍因素的理解 整个组织受到限制。细胞代谢是控制分化轨迹的一个因素 各种免疫细胞子集，但是它如何塑造TRM分化，持久性和功能尚未是 详细研究。我们先前鉴定出多胺代谢及其在氨基酸合成中的作用 无偶联是控制巨噬细胞代谢和激活的中央轴。我们还表明了无偶然 合成指导T细胞承担不同效应子命运的能力。这些发现照亮了无偶然的 免疫细胞命运和效应子计划的焦点协调员。然而，无偶联如何有助于组织 免疫力和TRM维护仍然未知。唯一含有量子素的蛋白质是翻译因子 EIF5A，其中保守的赖氨酸在两步过程中通过精子素在两步过程中被酶转化为非属。 无惯用的EIF5A促进具有特定序列特性的转录本的翻译。我们的目标 提案是通过解决无限的稳态和疾病中对TRM生物学的深入了解 代谢。我们的中心假设是，次量调节单核细胞衍生细胞的分化 TRM和/或它们在组织中的维持 益处疾病。我们以我们发表的工作和引人注目的初步数据为基础 合成控制了多个器官之间的巨噬细胞组织呈现。我们的方法将增加对 短寿命的前体细胞如何发展为长寿的TRM，从而对生命进行必不可少的功能。重要的是， 它将确定无偶合合成是否是在影响它们影响的情况下调节TRM的可拖动途径 疾病，例如与肿瘤相关的巨噬细胞和癌症。我们将通过1）检验我们的中心假设 研究量子合成在TRM形成和/或维持中的作用，2）探测机制 通过哪些造成巨噬细胞组织的遗留和3）检查是否操纵 巨噬细胞中的无酶合成有益于抗肿瘤免疫。