The function of mTORC1/Stat3 signaling in the regulation of fibrovascular scar formation during tendon healing

项目摘要/摘要 肌腱损伤是具有挑战性的临床问题，因为纤维血管瘢痕愈合缓慢且不完全。 形成，降低肌腱功能，并导致慢性并发症，如疼痛和肌腱断裂。 对纤维血管瘢痕形成的调节机制的有限理解是一个重要的 认识上的差距，阻碍了肌腱疾病有效治疗模式的发展。 纤维血管瘢痕组织的特征是细胞外基质(ECM)紊乱，细胞密度高， 新生血管。因此，迫切需要了解调控肌腱细胞和肌腱的关键因素。 肌腱愈合过程中细胞外基质的成熟，以发展再生医学。最近的研究表明 MTORC1(雷帕霉素复合体1的机械靶点)信号是出生后肌腱的关键调节因子 成熟性与致病性肌腱疾病有关，如屈肌腱纤维性粘连、脂肪 肩袖撕裂后的浸润性，以及人体肌腱病。然而，mTORC1在纤维血管中的作用 瘢痕的形成及其下游的分子机制尚不清楚。STAT3(信号传感器和 转录激活子3)参与了多种组织中纤维性瘢痕的形成，被称为 癌细胞中mTORC1信号的下游靶点。然而，没有报道的证据表明， STAT3介导mTORC1在肌腱纤维血管瘢痕形成中的作用。我们的总体目标是 明确mTORC1/STAT3信号通路在纤维血管瘢痕形成中的作用 MTORC1/STAT3调节对再生肌腱愈合的有利作用。的核心假说 建议的研究是：(I)损伤诱导的mTORC1信号调控纤维血管瘢痕的形成 肌腱愈合；(Ii)STAT3通过调节细胞外基质介导mTORC1在纤维血管瘢痕形成中的作用 组织。我们将使用创新的多学科方法来验证这一假设，包括鼠标 遗传学、手术损伤模型、先进的分子/成像分析和生物力学测试。的目标是 目的：探讨肌腱愈合过程中mTORC1在纤维血管瘢痕形成中的作用。目标是 AIM2的目的是将STAT3定义为肌腱纤维血管瘢痕形成中mTORC1功能的介体。这个 拟议研究的成功将极大地促进对纤维血管机制的理解 肌腱愈合过程中瘢痕的形成，为翻译和临床研究提供了新的平台 针对mTORC1/STAT3信号通路治疗衰弱肌腱疾病的研究。

Project Summary/Abstract Tendon injuries are challenging clinical problems due to slow, incomplete healing with fibrovascular scar formation, which reduces tendon function and causes chronic complications such as pain and tendon ruptures. The limited understanding of the regulatory mechanisms underlying fibrovascular scar formation is a significant gap in knowledge, hindering the development of effective treatment modalities for tendon diseases. Fibrovascular scar tissue is characterized by a disorganized extracellular matrix (ECM) with high cellularity and neovascularization. Therefore, there is a critical need to understand the key factors regulating tendon cells and ECM maturation during tendon healing to develop regenerative medicine. Recent studies have demonstrated that mTORC1 (mechanistic target of rapamycin complex 1) signaling is a critical regulator for postnatal tendon maturation and is associated with pathogenic tendon conditions such as fibrotic adhesion of flexor tendon, fatty infiltration after rotator cuff tears, and human tendinopathy. However, the function of mTORC1 in fibrovascular scar formation and its downstream molecular mechanisms are not known. Stat3 (signal transducer and activator of transcription 3) is involved in fibrotic scar formation in multiple tissues and is known as a downstream target of mTORC1 signaling in cancer cells. However, there is no reported evidence showing that Stat3 mediates the function of mTORC1 in fibrovascular scar formation in tendons. Our overall objective is to define the function of the mTORC1/Stat3 signaling cascade in fibrovascular scar formation and evaluate the beneficial effects of mTORC1/Stat3 modulation on regenerative tendon healing. The central hypothesis of the proposed research is that (i) injury-induced mTORC1 signaling governs fibrovascular scar formation during tendon healing, and (ii) Stat3 mediates mTORC1 function in fibrovascular scar formation via regulation of ECM organization. We will test the hypothesis using innovative multidisciplinary approaches, including mouse genetics, a surgical injury model, advanced molecular/imaging analyses, and a biomechanical test. The goal of Aim1 is to determine the function of mTORC1 in fibrovascular scar formation during tendon healing. The goal of Aim2 is to define Stat3 as a mediator of mTORC1 function in fibrovascular scar formation in tendons. The success of the proposed research will significantly advance the mechanistic understanding of fibrovascular scar formation during tendon healing and provide a new platform to develop translational and clinical researches targeting the mTORC1/Stat3 signaling cascade for the treatment of debilitating tendon diseases.