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/文摘