Muscle Tregs in health and disease

健康和疾病中的肌肉 Tregs

基本信息

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
项目类别：
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

项目摘要

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.

除了抵抗微生物挑战的主要功能外，免疫系统还发挥着重要作用长期以来，人们一直认为巨噬细胞可以发挥这种辅助作用。功能，并且在过去几年中，人们对 Foxp3+CD4+ 的含义越来越感兴趣稳态过程中的调节性 T 细胞（或 Tregs）例如，许多独特的 Treg 区室。实质组织的活性促进急性或慢性损伤后的局部修复/再生——即使在斑马鱼中也是如此！骨骼肌 Tregs 是典型的促再生调节性 T 细胞群。我们实验室2012年报道，与淋巴器官不同，急性损伤后肌肉Treg细胞迅速增加 Tregs 的代表性提高、组织适应的转录组、独特的（克隆扩展的）T 细胞受体库和生长/生存因子依赖性，是在上一期中发现的。资金周期，需要伤害性神经元产生肽 CGRP，从而引发 IL-33 的产生；基质细胞；进而促进局部 Treg 积累。组织修复过程——在早期、促炎、以及晚期、促再生阶段。这种广泛的活动凸显了超越当前的必要性。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（在上一个融资周期生成）揭示了五种不同的子类型，这些子类型随着时间的推移而盛衰：循环的、最近激活的、RORγ+、T-bet+ 和 GATA3+（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与相邻亚型整合我们的总体假设是，淋巴和非淋巴细胞促进肌肉再生。个别亚型的出现和/或扩展是为了处理在过程中出现的特定生物学问题修复/再生过程尤其旨在： 1. 确定 RORγ+ 骨骼肌 Tregs 的来源。 2. 确定 RORγ+ Tregs 在有效的肌肉修复/再生中发挥什么关键作用。 3. 确定内源性 CGRP 是否协调肌肉 MSC 和 IL-33 产量的增加随后修复性 (GATA3+) 肌肉 Treg 亚型的扩展。完成这些研究将为我们提供更准确、更细致的 Treg 活动图景在肌肉再生过程中，潜在的治疗应用有很多：灾难性伤口愈合、运动- 诱发损伤、年龄相关性肌少症、肌营养不良、自身免疫性肌炎和慢性肌肉萎缩症感染。