Muscle Tregs in health and disease

健康和疾病中的肌肉 Tregs

基本信息

批准号：
9268650
负责人：
DIANE J MATHIS
金额：
$ 37.29万
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 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9268650
关键词：
Ablation Acute Adaptive Immune System Address Adipose tissue Affect Age Aging Amphiregulin Amyotrophic Lateral Sclerosis Animals Behavior Binding Biological Assay CD4 Positive T Lymphocytes Cell Compartmentation Cells Characteristics Chronic Data Denervation Disease Duchenne muscular dystrophy Elderly Endothelial Cells Evaluation FOXP3 gene Goals Growth Health Heterogeneity Homeostasis Human Immune response In Vitro Injury Link Mediator of activation protein Metabolic Mining Modeling Mus Muscle Muscle Cells Muscle Spindles Muscular Dystrophies Myopathy Natural regeneration Nerve Neurons Paint Pathogenesis Pathology Patients Pattern Phenotype Population Process Regulatory T-Lymphocyte Role Skeletal Muscle Societies Stem cells Structure Supplementation T-Cell Receptor T-Lymphocyte Testing Therapeutic Visceral aged beta-site APP cleaving enzyme 1 cell type cytokine experimental study improved in vivo indexing injured loss of function muscle form muscle regeneration receptor reduced muscle mass repaired response transcription factor transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY/ABSTRACT Foxp3+CD4+ regulatory T (Treg) cells control most types of immune responses, influencing the activities of both innate and adaptive cell-types. Evidence is mounting that special classes of Tregs also regulate non- immunological processes in non-immunological cells – and, as a consequence, organismal homeostasis. The best characterized example to date is a Foxp3+CD4+ population that resides in visceral adipose tissue and regulates local and systemic metabolic indices. Recently, a distinct Treg population was identified in murine skeletal muscle. Muscle Tregs are highly enriched within the local CD4+ T cell compartment, and have a distinctive T cell receptor repertoire and transcriptome. They regulate muscle regeneration in response to both acute and chronic injury, affecting the behavior of infiltrating innate cells as well as impacting muscle progenitor cells, at least in part via secretion of the growth/survival factor, Amphiregulin. An analogous population of Foxp3+CD4+ T cells has been identified in humans, enriched in patients with Duchenne muscular dystrophy. Preliminary data provide strong evidence that IL-33 controls Treg accumulation in injured skeletal muscle. For example, this cytokine is deficient in muscles of geriatric mice, as are Tregs, partially explaining the poor muscle repair characteristic of old animals; and this cytokine’s experimental supplementation coincident with injury significantly improves muscle repair/regeneration. Il-33 has an intriguing pattern of expression in muscle: primarily in fibro/adipogenic progenitor cells, often (though not always) in close association with archetypal nerve structures, such as nerve bundles and muscle spindles. The major goal of this proposed project is to elucidate the cellular and molecular interactions between Tregs and IL-33-producing cells during acute and chronic muscle injury. This goal will be addressed in the framework of three Specific Aims: 1) to paint a more precise picture of IL-33-producing cells in skeletal muscle; 2) to evaluate the functional relevance of the physical association between IL-33-producers and nerve structures in muscle, and 3) to explore the role of IL- 33 in a chronic muscle disease. Successful completion of these Aims stands to advance our understanding, and potential treatment, of several muscle pathologies – including the reduced muscle mass, function and repair of the aged, muscular dystrophies such as Duchenne muscular dystrophy, and potentially Amyotrophic Lateral Sclerosis.

项目概要/摘要 Foxp3+CD4+ 调节性 T (Treg) 细胞控制大多数类型的免疫反应，影响活动越来越多的证据表明，特殊类别的 Tregs 也调节非细胞类型。非免疫细胞中的免疫过程 - 以及由此产生的生物体内平衡。迄今为止最有特征的例子是存在于内脏脂肪组织中的 Foxp3+CD4+ 群体调节局部和全身代谢指标最近，在小鼠中发现了独特的 Treg 群体。肌肉 Tregs 在局部 CD4+ T 细胞区室中高度富集，并且具有它们通过独特的 T 细胞受体库和转录组来调节肌肉再生。急性和慢性损伤，影响浸润先天细胞的行为以及影响肌肉祖细胞细胞，至少部分通过生长/生存因子双调蛋白的分泌。 Foxp3+CD4+ T 细胞已在人类中被发现，在杜氏肌营养不良症患者中富集。初步数据提供了强有力的证据，表明 IL-33 控制受损骨骼肌中 Treg 的积累。例如，老年小鼠的肌肉中缺乏这种细胞因子，Tregs 也是如此，这部分解释了老年小鼠的肌肉缺乏这种细胞因子。老年动物的肌肉修复特征；与该细胞因子的实验补充相吻合；损伤可改善肌肉修复/再生。IL-33 在肌肉中具有有趣的表达模式：主要存在于纤维/脂肪形成祖细胞中，通常（但并非总是）与原型密切相关该项目的主要目标是神经结构，例如神经束和肌梭。阐明急性期 Treg 和产生 IL-33 的细胞之间的细胞和分子相互作用这一目标将在三个具体目标的框架内得到解决：1）绘制一个骨骼肌中产生 IL-33 的细胞的更精确图像；2) 评估 IL-33 产生者和肌肉神经结构之间的物理关联，以及 3) 探索 IL-33 的作用 33 在慢性肌肉疾病中，成功完成这些目标将增进我们的理解，以及几种肌肉病理学的潜在治疗方法——包括肌肉质量、功能和功能的减少修复老年性肌营养不良症，如杜氏肌营养不良症和潜在的肌营养不良症侧索硬化症。