Role of regulatory T cells in tendon regeneration

调节性 T 细胞在肌腱再生中的作用

• 批准号: 9911064
• 负责人: Varun Arvind
• 金额: $ 4.55万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-27 至 2023-02-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911064
• 关键词: Ablation; Acute; Adult; Anti-Inflammatory Agents; Bioinformatics; Biological Assay; Biological Response Modifiers; Cell Proliferation; Cells; Cicatrix; Clinical; Complement; Dexamethasone; Diphtheria Toxin; Disease; Elderly; Environment; Enzyme-Linked Immunosorbent Assay; Exhibits; FDA approved; FOXP3 gene; Fellowship; Flow Cytometry; Gait; Gene Expression Profile; Genes; Genetic Transcription; Gold; Homeostasis; Immune; Immune response; Immunotherapeutic agent; Individual; Inflammatory; Injury; Maps; Mechanics; Mediating; Modeling; Molecular; Mus; Muscle; Natural regeneration; Neonatal; Operative Surgical Procedures; Outcome; Pattern; Pharmacy (field); Phenotype; Population; Property; Regulatory T-Lymphocyte; Role; Site; Spleen; T-Lymphocyte; Tamoxifen; Tendinopathy; Tendon Injuries; Tendon structure; Testing; Time; Tissues; United States; Work; base; functional restoration; genetic signature; healing; immunoregulation; improved; in vivo; injured; interest; macrophage; mouse model; named group; neonatal immunity; neonatal injury; neonate; novel; parent grant; polarized light; programs; recruit; regenerative; repaired; response; response to injury; standard care; tendon rupture; tissue repair; transcription factor; transcriptome sequencing; transcriptomics; wound; wound healing

Summary Achilles tendinopathy is a common degenerative change seen in athletes and elderly individuals. Tendons have limited regenerative capacity and heal via the formation of a disorganized, fibrotic scar. Surgical options for tendinopathy are often ineffective and rates of re- injury after surgical intervention are high. While the clinical changes associated with tendinopathy are well characterized, the mechanisms that underpin tendon healing remain poorly understood. In an effort to understand the cellular and molecular mechanisms that control tendon healing, our lab has developed a regenerative model of tendon healing in neonatal mice to complement existing fibrotic models of tendon healing in adult mice. Interestingly, a growing body of evidence has demonstrated that neonatal immunity uniquely supports a pro- regenerative, anti-fibrotic phenotype. Preliminary work from our lab similarly suggests that the immune response is critical to tendon healing. Moreover, neonatal response to injury in tendon differs dramatically from adult, and Tregs may underlie this difference in immune landscape. Therefore, we hypothesize that tendon specific Tregs involved in neonatal regeneration represent a special population of Tregs, unique in their capacity to promote regeneration (Aim 1). Next, we hypothesize that Tregs are necessary for neonatal tendon regeneration (Aim 2), and that establishment of a neonatal immune landscape in adult mice using dexamethasone, can rescue tendon regeneration in adults (Aim 3).

摘要 跟腱病是运动员和老年人常见的退行性改变。 个人。肌腱再生能力有限，可通过形成肌腱 散乱的纤维性疤痕。肌腱病的手术选择往往无效，复发率 手术干预后伤害率较高。而与之相关的临床变化 肌腱病的特征很好，支撑肌腱愈合的机制仍然存在 人们对此知之甚少。为了了解控制细胞和分子的机制 肌腱愈合，我们实验室建立了新生小鼠肌腱愈合的再生模型 以补充现有的成年小鼠肌腱愈合的纤维化模型。有趣的是，一个不断增长的 大量证据表明，新生儿免疫独特地支持一种有利于- 再生的，抗纤维化的表型。我们实验室的初步工作同样表明， 免疫反应是肌腱愈合的关键。此外，新生儿对肌腱损伤的反应 与成虫有很大的不同，特雷格可能是这种免疫格局的基础。 因此，我们假设肌腱特异性Tregs参与了新生儿的再生。 代表一个特殊的树人群体，其促进再生的能力是独一无二的(目标 1)。接下来，我们假设Tregs是新生儿肌腱再生所必需的(目标2)， 以及使用地塞米松在成年小鼠中建立新生免疫环境， 可以挽救成人的肌腱再生(目标3)。