Muscle Tregs in health and disease

健康和疾病中的肌肉 Tregs

• 批准号: 10333370
• 负责人: DIANE J MATHIS
• 金额: $ 36.88万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10333370
• 关键词: Acute; Address; Age; Aging; Antibiotics; Autoimmune; Biological; Blood Circulation; Brain; Calcitonin Gene-Related Peptide; Chronic; Colon; Data; Dependence; Disease; Event; Exercise; FOXP3 gene; Fibrosis; Funding; GATA3 gene; Goals; Growth; Health; Homeostasis; Image; Immigration; Immune response; Immune system; Impairment; Individual; Infection; Infiltration; Inflammatory; Inflammatory Infiltrate; Injury; Knock-out; Knockout Mice; Leukocytes; Lymphoid; Modeling; Mus; Muscle; Muscle satellite cell; Muscular Dystrophies; Myocardium; Natural regeneration; Nerve; Nervous system structure; Nociceptors; Peptide Signal Sequences; Peptides; Pharmacology; Phase; Phenotype; Play; Population; Process; Production; Regulatory T-Lymphocyte; Reporting; Role; Signal Transduction; Skeletal Muscle; Skin; Societies; Stromal Cells; System; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Testing; Therapeutic; Time; Tissues; Waxes; Zebrafish; age related; conditional knockout; design; experimental study; fighting; gut microbiota; inhibitor; interest; lymphoid organ; macrophage; mesenchymal stromal cell; microbial; muscle form; muscle regeneration; orphan nuclear receptor ROR-gamma; pain perception; regenerative; repaired; sarcopenia; single-cell RNA sequencing; tissue regeneration; tissue repair; transcriptome; transcriptomics; wound; wound healing

Beyond its primary function of repelling microbial challenges, the immune system plays important roles in safeguarding tissue homeostasis. Macrophages have long been recognized to exercise such secondary functions and, over the past several years, there has been growing interest in the implication of Foxp3+CD4+ regulatory T cells (or Tregs) in homeostatic processes. For example, unique Treg compartments in a number of parenchymal tissues promote local repair/regeneration after acute or chronic injury – even in zebrafish! Skeletal-muscle Tregs serve as a paradigmatic pro-regenerative regulatory T cell population. First reported by our lab in 2012, muscle Tregs increase rapidly after acute injury, differing from lymphoid-organ Tregs in their elevated representation, tissue-adapted transcriptome, distinct – clonally expanded – T cell receptor repertoire, and growth/survival factor dependencies. One intriguing axis, discovered during the last funding-cycle, entails nociceptive neuron production of the peptide, CGRP; which elicits IL-33 production from stromal cells; which, in turn, promotes local Treg accumulation. Muscle Tregs exert multiple influences along the course of tissue repair – on both lymphoid and non-lymphoid cells during both the early, pro-inflammatory, and late, pro-regenerative, phases. This broad range of activities highlights the need to go beyond the current static image of muscle-Treg phenotype and function to obtain a dynamic view spanning the entire process. Temporal single-cell RNAseq data on the muscle-Treg compartment from 1-14 days post-injury (generated during the last funding-cycle) revealed five distinct subtypes that waxed and waned over time: circulating, recently activated, RORγ+, T-bet+ and GATA3+ (or reparative). Our long-term goal is to understand how the five muscle-Treg subtypes integrate with each other and with neighboring lymphoid and non-lymphoid cells to promote muscle regeneration. Our overall hypothesis is that individual subtypes emerge and/or expand to deal with particular biological issues that arise during the repair/regeneration process. In particular, this proposed project aims to: 1. Identify the provenance of RORγ+ skeletal-muscle Tregs. 2. Determine what critical role(s) RORγ+ Tregs play in effective muscle repair/regeneration. 3. Determine whether endogenous CGRP orchestrates increased IL-33 production by muscle MSCs and consequent expansion of the reparative (GATA3+) muscle-Treg subtype. Completion of these studies will provide us with a more accurate and nuanced picture of Treg activities during muscle regeneration. Potential therapeutic applications are many: catastrophic wound healing, exercise- induced damage, age-related sarcopenias, muscular dystrophies, autoimmune myositides and chronic muscle infections.

除了抵御微生物挑战的主要功能外，免疫系统还发挥着重要作用 保护组织的稳态长期以来，人们一直认为， 在过去的几年里，人们对Foxp 3 + CD 4+的影响越来越感兴趣。 调节性T细胞（或Tcells）在体内平衡过程中的作用。例如，在一个数字中的独特Treg区室 促进急性或慢性损伤后的局部修复/再生-即使在斑马鱼！ 骨骼肌T细胞是一种典型的促再生调节性T细胞群。第一 2012年，本实验室报道，急性损伤后，肌肉TdR迅速增加，与淋巴器官不同， T细胞在其升高的代表性，组织适应性转录组，独特的克隆扩增- T细胞 受体库和生长/存活因子依赖性。一个有趣的轴，发现在过去的 在免疫反应中，免疫反应是一个重要的过程，需要伤害性神经元产生肽CGRP，这促进了IL-33的产生。 基质细胞;这反过来又促进局部Treg积累。肌肉张力沿着施加多重影响 组织修复过程-在早期，促炎， 和后期的促再生阶段。这一广泛的活动突出表明，需要超越目前的 肌肉-Treg表型和功能的静态图像，以获得跨越整个过程的动态视图。 损伤后1-14天肌肉-Treg区室的时间单细胞RNAseq数据 （上一个供资周期生成的）显示，随着时间的推移，五种不同的亚型出现了消长： 循环的，最近激活的，RORγ+，T-bet+和GATA 3+（或修复性）。我们的长期目标是 了解五种肌肉Treg亚型如何相互整合，以及如何与邻近的 淋巴和非淋巴细胞，以促进肌肉再生。我们的总体假设是 个体亚型出现和/或扩展以处理在治疗期间出现的特定生物学问题， 修复/再生过程。具体而言，拟议项目旨在： 1.鉴定RORγ+猪肌肉TdR的来源。 2.确定RORγ+ TdR在有效的肌肉修复/再生中发挥的关键作用。 3.确定内源性CGRP是否协调增加肌肉MSC的IL-33产生， 随后的修复性（GATA 3+）肌肉-Treg亚型的扩增。 这些研究的完成将为我们提供更准确和细致入微的Treg活动图片 在肌肉再生过程中。潜在的治疗应用有很多：灾难性的伤口愈合，运动- 诱发损伤、年龄相关性肌肉减少症、肌营养不良症、自身免疫性肌炎和慢性肌肉萎缩症 感染.