The role of T cells in tendon healing

T细胞在肌腱愈合中的作用

• 批准号: 10753749
• 负责人: Alice H Huang
• 金额: $ 58.66万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753749
• 关键词: Adoptive Transfer; Adult; Affect; Anti-Inflammatory Agents; Antigen-Presenting Cells; Biological; CD4 Positive T Lymphocytes; Cell Communication; Cells; Chronic; Cicatrix; Clinical; Collagen; Data; Dendritic Cells; Environment; Event; Exhibits; FOXP3 gene; Fibrosis; Flow Cytometry; Gait; Genetic; Image; Immune; Immune response; Impairment; In Vitro; Inflammation; Inflammatory; Injury; Life; Macrophage; Mediating; Modeling; Molecular; Mus; Myofibroblast; Natural regeneration; Neonatal; Outcome; Pain; Pathologic; Pilot Projects; Population; Proliferating; Recombinants; Recovery; Recurrence; Regulatory T-Lymphocyte; Research; Research Priority; Resolution; Role; Rupture; Signal Transduction; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; TCF Transcription Factor; Tendinopathy; Tendon Injuries; Tendon structure; Testing; Tissues; functional restoration; healing; immunological synapse; immunological synapse formation; immunoregulation; improved; migration; neonatal mice; neonate; novel; permissiveness; receptor-mediated signaling; recruit; regenerative; repaired; response; single-cell RNA sequencing; stem cells; tendon rupture; wound healing

PROJECT SUMMARY Tendon injury is a common problem characterized by slow recovery and high recurrence. Improving tendon healing to a functionally effective state is therefore a crucial research priority, however the basic biological mechanisms remain unknown. Our overall objective is therefore to identify the cellular and molecular events that distinguish healing mechanisms to improve adult tendon healing. One key feature in all wound healing is the immune environment. Injury initially induces an inflammatory type 1 response, followed by transition to an anti-inflammatory type 2 response. Imbalanced type 1 or type 2 responses are often associated with fibrotic healing or degeneration. To date, T cells have rarely been investigated, even though T cell subpopulations regulate type 1 and type 2 immune responses, macrophage polarization, and in some cases can directly active tissue-resident stem cells. Due to this gap in research, the mechanisms by which specific immune cell populations create permissive environments for effective and poor healing are not known, especially for poor healing tissues such as tendon. We previously established novel models of effective tendon healing (neonatal mouse) and fibrosis (adult mouse), and identified cellular mechanisms that distinguish these. Based on rigorous pilot data, we now hypothesize that T cell subpopulations mediate tendon healing through direct and indirect interactions with tenocytes and by mediating effective tendon healing or chronic inflammation via IL33- dependent mechanisms. To test these hypotheses, we will define the role of neonatal vs adult T cell populations and T cell-tenocyte interactions after tendon injury (Aim 1), elucidate the mechanisms of Treg- mediated resolution of IL33 in tendon healing (Aim 2), and determine the pathological consequences of chronic IL33 inflammation in tendon healing (Aim 3)

项目摘要 肌腱损伤是一个常见的问题，其特征是缓慢恢复和高复发。改进 因此 生物学机制仍然未知。因此，我们的总体目标是确定细胞和 分子事件区分了改善成人肌腱愈合的愈合机制。 所有伤口愈合中的一个关键特征是免疫环境。受伤最初引起炎症 1型响应，然后过渡到抗炎2型响应。不平衡的类型1或 2型反应通常与纤维化愈合或变性有关。迄今为止，T细胞具有 即使T细胞亚群调节1型和2型免疫，也很少研究 反应，巨噬细胞极化以及在某些情况下可以直接活跃的组织居住的干细胞。到期的 对于研究的这一差距，特定免疫细胞群体的机制 尚不清楚有效和康复不良的宽容环境，尤其是因为治愈不佳 组织，例如肌腱。 我们以前建立了有效肌腱愈合（新生小鼠）和 纤维化（成年小鼠），并确定了区分这些区域的细胞机制。基于严格的飞行员数据， 现在，我们假设T细胞亚群通过直接和间接介导肌腱愈合 通过介导有效的肌腱愈合或通过IL33-介导有效的肌腱愈合或慢性炎症来相互作用 依赖机制。为了检验这些假设，我们将定义新生儿与成人T细胞的作用 肌腱损伤后的群体和T细胞 - 诱细胞相互作用（AIM 1）阐明了Treg-的机制 肌腱愈合中IL33的介导分辨率（AIM 2），并确定 肌腱愈合中的慢性IL33炎症（AIM 3）