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

mTORC1/Stat3信号在肌腱愈合过程中纤维血管疤痕形成调节中的作用

• 批准号: 10444013
• 负责人: Kyu Sang Joeng
• 金额: $ 35.75万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444013
• 关键词: 3-Dimensional; Adhesions; Area; Biological; Cells; Cellularity; Chronic; Cicatrix; Clinical; Clinical Research; Complex; Data; Development; Disease; Extracellular Matrix; FRAP1 gene; Fibroblasts; Flexor; Gene Expression; Genetic; Genetic Models; Genetic Transcription; Genetic study; Goals; Human; Image; Infiltration; Injury; Knowledge; Malignant Neoplasms; Mediating; Mediator of activation protein; Modality; Modeling; Molecular; Molecular Analysis; Molecular Genetics; Mus; Operative Surgical Procedures; Outcome; Pain; Pathogenicity; Pharmacology; Pharmacology Study; Phenotype; Regenerative Medicine; Regulation; Reporting; Research; Signal Transduction; Stat3 protein; Surgical Injuries; Targeted Research; Tendinopathy; Tendon Injuries; Tendon structure; Testing; Tissues; Transcriptional Regulation; Translational Research; base; biomechanical test; cancer cell; clinically significant; effective therapy; experimental study; gain of function; healing; in vivo; innovation; interdisciplinary approach; loss of function; molecular imaging; mouse genetics; mouse model; neovascularization; novel; patellar tendon; postnatal; regenerative; rotator cuff tear; success; tendon development; tendon rupture; therapeutic target; translational approach; wound

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.

项目总结/摘要 肌腱损伤是具有挑战性的临床问题，由于缓慢，不完全愈合与纤维血管疤痕 形成，这降低了肌腱功能，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控机制的有限理解是一个重要的问题。 知识的差距，阻碍了肌腱疾病的有效治疗方式的发展。 纤维血管性瘢痕组织的特征在于具有高细胞性的紊乱的细胞外基质（ECM）， 新生血管形成因此，迫切需要了解调节肌腱细胞的关键因素， 肌腱愈合过程中ECM成熟，以开发再生医学。最近的研究表明 mTORC 1（雷帕霉素复合物1的机制靶点）信号传导是出生后肌腱的关键调节因子， 并且与致病性肌腱病症如屈肌腱的纤维化粘连、脂肪性粘连、纤维性粘连、纤维性粘连等相关。 肩袖撕裂后的浸润和人类肌腱病。然而，mTORC 1在纤维血管中的功能 瘢痕形成及其下游分子机制尚不清楚。Stat 3（信号传感器和 转录激活因子3）参与多种组织中的纤维化瘢痕形成，并且被称为 mTORC 1信号转导的下游靶点。然而，没有证据表明， Stat 3介导mTORC 1在肌腱纤维血管瘢痕形成中的功能我们的总体目标是 明确mTORC 1/Stat 3信号级联在纤维血管性瘢痕形成中的作用， mTORC 1/Stat 3调节对再生肌腱愈合的有益作用。的中心假设 拟议的研究是：（i）损伤诱导的mTORC 1信号转导调控纤维血管瘢痕形成， 肌腱愈合，以及（ii）Stat 3通过调节ECM介导mTORC 1在纤维血管瘢痕形成中的功能 organization.我们将使用创新的多学科方法来测试这一假设，包括小鼠实验。 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 目的1是确定mTORC 1在肌腱愈合过程中纤维血管瘢痕形成中的功能。目标 目的2是将Stat 3定义为肌腱中纤维血管瘢痕形成中mTORC 1功能的介导物。的 这项研究的成功将大大推进对纤维血管的机制的理解。 肌腱愈合过程中的瘢痕形成，并提供了一个新的平台，开发翻译和临床 靶向mTORC 1/Stat 3信号级联的研究，用于治疗衰弱性肌腱疾病。