The role of T cells in tendon healing

项目总结 肌腱损伤是一种常见的问题，其特点是恢复慢，复发率高。改进 因此，肌腱愈合到功能有效的状态是一个关键的研究重点，然而基础 生物机制仍不清楚。因此，我们的总体目标是识别细胞和 分子事件区分愈合机制，以促进成人肌腱愈合。 所有伤口愈合的一个关键特征是免疫环境。损伤最初会导致炎症 第一型反应，然后过渡到抗炎第二型反应。不平衡类型1或 2型反应通常与纤维性愈合或变性有关。到目前为止，T细胞已经 很少被研究，即使T细胞亚群调节1型和2型免疫 反应，巨噬细胞极化，在某些情况下可以直接激活组织驻留的干细胞。到期 针对这一研究差距，特定的免疫细胞群体产生 有效和不良愈合的允许环境是未知的，尤其是不良愈合。 肌腱等组织。 我们以前建立了有效的肌腱愈合的新模型(新生小鼠)和 纤维化(成年小鼠)，并确定区分这些的细胞机制。基于严格的飞行员数据， 我们现在假设T细胞亚群通过直接和间接方式介导肌腱愈合 与肌腱细胞的相互作用，并通过IL33-介导有效的肌腱愈合或慢性炎症 依赖机制。为了验证这些假设，我们将定义新生儿和成人T细胞的作用 肌腱损伤后的群体和T细胞-肌腱细胞的相互作用(目标1)，阐明Treg-TERG的机制。 介导IL33在肌腱愈合中的分解(目标2)，并确定 肌腱愈合中的慢性白介素33炎症(目标3)

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)