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: 10554422
• 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/10554422
• 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; Mediating; Mediator; Modality; Modeling; Molecular; Molecular Analysis; Mus; Operative Surgical Procedures; Outcome; Pain; Pathogenicity; Pharmacology Study; Phenotype; Qualifying; Regenerative Medicine; Regulation; Reporting; Research; STAT1 protein; Signal Transduction; Stat3 protein; Surgical Injuries; Targeted Research; Tendinopathy; Tendon Injuries; Tendon structure; Testing; Tissues; Transcriptional Regulation; Translational Research; biomechanical test; cancer cell; clinically significant; effective therapy; experimental study; gain of function; healing; in vivo; innovation; interdisciplinary approach; loss of function; mouse genetics; mouse model; neovascularization; novel; patellar tendon; pharmacologic; 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.

项目摘要/摘要 由于纤维血管疤痕缓慢，不完全治愈，肌腱损伤是挑战临床问题 形成，可降低肌腱功能并导致慢性并发症，例如疼痛和肌腱破裂。 对纤维血管形成的调节机制的有限理解是重要的 知识差距，阻碍了肌腱疾病有效治疗方式的发展。 纤维血管疤痕组织的特征是细胞外基质（ECM）高细胞和高细胞的特征 新血管形成。因此，迫切需要了解调节肌腱细胞的关键因素，并且 肌腱愈合期间的ECM成熟以开发再生医学。最近的研究表明 MTORC1（雷帕霉素复合物的机理目标1）信号传导是产后肌腱的关键调节剂 成熟，与致病性肌腱条件（例如屈肌的纤维化粘附，脂肪）有关 肩袖撕裂和人肌腱病后的浸润。但是，MTORC1在纤维血管中的功能 疤痕形成及其下游分子机制尚不清楚。 STAT3（信号传感器和 转录的激活剂3）参与多个组织中的纤维化疤痕形成，被称为 癌细胞中MTORC1信号传导的下游靶标。但是，没有报道证据表明 STAT3介导MTORC1在肌腱中形成纤维血管疤痕中的功能。我们的总体目标是 定义纤维血管疤痕形成中MTORC1/STAT3信号级联的功能并评估 MTORC1/STAT3调制对再生肌腱愈合的有益影响。中心假设 拟议的研究是（i）受伤诱导的MTORC1信号传导控制纤维血管疤痕 肌腱愈合，（ii）STAT3通过调节ECM介导了纤维血管疤痕中MTORC1的功能 组织。我们将使用创新的多学科方法来检验假设，包括鼠标 遗传学，外科损伤模型，晚期分子/成像分析和生物力学检测。目标 AIM1是在肌腱愈合过程中确定MTORC1在纤维血管疤痕形成中的功能。目标 AIM2的内容是将STAT3定义为肌腱纤维血管疤痕形成中MTORC1功能的介体。这 拟议研究的成功将显着提高纤维血管的机理理解 肌腱愈合期间的疤痕形成，并提供了一个新的平台来发展转化和临床 针对MTORC1/STAT3信号级联的研究用于治疗衰弱的肌腱疾病。