Pathologic Role of Inflammation and Mechanistic Analysis of Myofibroblastogenesis in Arthrofibrosis

炎症的病理作用及肌纤维母细胞发生在关节纤维化中的机制分析

• 批准号: 10359048
• 负责人: Matthew P Abdel
• 金额: $ 34.63万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359048
• 关键词: Achievement; Address; Adjuvant Therapy; Adult; Alternative Therapies; Animal Model; Animals; Anti-Inflammatory Agents; Antiinflammatory Effect; Biological; Biomechanics; Biopsy; Blood Vessels; Cells; Cellular Structures; Cicatrix; Clinical; Coculture Techniques; Complication; Connective Tissue; Contracture; Custom; Data; Defect; Development; Differentiation and Growth; Disease; Disease Progression; Drug Monitoring; Early Intervention; Effector Cell; Environment; Event; Excision; Fibroblasts; Fibrosis; Goals; Growth; Growth Factor; Heart; Hematopoietic; Histologic; Human; Immune system; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Intervention; Intrinsic drive; Joints; Kidney; Knowledge; Laboratories; Lead; Link; Lung; Mechanics; Mediating; Mesenchymal Stem Cells; Modeling; Molecular; Molecular Analysis; Monitor; Myofibroblast; Non-Steroidal Anti-Inflammatory Agents; Normal tissue morphology; Operative Surgical Procedures; Oryctolagus cuniculus; Pathogenesis; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phosphotransferases; Physiological; Primary Cell Cultures; Procedures; Process; Prophylactic treatment; Prostaglandins; Regulator Genes; Repeat Surgery; Risk Factors; Role; Signaling Protein; Testing; Time; Tissues; Trauma; Work; base; celecoxib; cell growth; cell type; cost; gene regulatory network; genetic regulatory protein; healing; human data; in vitro Model; in vivo; inhibitor; innovation; insight; joint injury; knee replacement arthroplasty; macrophage; mast cell; mesenchymal stromal cell; novel; novel marker; prevent; recruit; repaired; response; scaffold; tissue repair

ABSTRACT Arthrofibrosis is a very prevalent debilitating complication of routine total knee arthroplasty. Our laboratory develops mechanism-based strategies for (i) treatment of arthrofibrosis, (ii) early intervention when the disease process is initiated, and (iii) identification of novel biomarkers that permit the monitoring of disease progression. We will address a major knowledge gap by addressing the central hypothesis that arthrofibrosis is initiated in vivo by local alterations in inflammation-related tissue repair processes after joint surgery. We propose that inflammatory processes modulate formation of mechano-protective transient connective tissues and that deregulation of normal joint tissue healing results in alterations in the growth, differentiation and activity of (proto)myofibroblasts that may emerge from the perivascular compartment of synovial tissues. To understand the mechanisms contributing to arthrofibrosis, we will analyze (i) the pathologic roles of inflammatory processes in a rabbit model for arthrofibrosis (Aim 1); and (ii) mechanisms of myofibroblastogenesis that are deregulated during arthrofibrosis by molecular analyses of biopsies and primary cell cultures from patients undergoing revision TKAs for arthrofibrosis, as well as established in vitro models for myofibroblast proliferation and differentiation in culture, as well as co-culture models with mast cells involved in the initial inflammatory response during tissue repair (Aim 2). The key deliverables of this proposal are translational innovation (Aim 1) by establishing (i) the mechanistic role of inflammation in arthrofibrosis and (ii) characterization of the potential efficacy of anti-inflammatory drugs to mitigate or reverse disease progression. Furthermore, this study is conceptually innovative (Aim 2) by establishing (iii) cell structure-linked kinase-mediated signaling pathways and gene regulatory networks that mediate myofibroblast differentiation in joint tissues, and (iv) functional consequences of inhibiting key regulatory proteins that drive the intrinsic ability of fibroblasts to convert to myofibroblasts.

抽象的 关节纤维化是常规全膝关节置换术中非常普遍的使人衰弱的并发症。我们的实验室 制定基于机制的策略，用于（i）治疗关节纤维化，（ii）疾病发生时的早期干预 启动该过程，并且（iii）鉴定允许监测疾病的新型生物标志物 进展。我们将通过解决以下中心假设来解决主要的知识差距： 关节纤维化是由炎症相关组织修复过程的局部改变在体内引发的 关节手术后。我们认为炎症过程调节机械保护的形成 暂时性结缔组织和正常关节组织愈合的失调会导致 可能从血管周围出现的（原）肌成纤维细胞的生长、分化和活性 滑膜组织的隔室。 为了了解导致关节纤维化的机制，我们将分析（i） 兔关节纤维化模型中的炎症过程（目标 1）； (ii) 机制 通过活检和原发性的分子分析，发现在关节纤维化过程中肌纤维母细胞发生失调 来自接受关节纤维化修正 TKA 的患者的细胞培养物，以及建立的体外模型 培养中肌成纤维细胞的增殖和分化，以及与肥大细胞参与的共培养模型 组织修复过程中的初始炎症反应（目标 2）。 该提案的主要成果是通过建立 (i) 机制实现转化创新（目标 1） 炎症在关节纤维化中的作用以及 (ii) 抗炎药物潜在功效的表征 以减轻或逆转疾病进展。此外，本研究在概念上具有创新性（目标 2） 建立（iii）细胞结构相关的激酶介导的信号传导途径和基因调控网络 介导关节组织中的肌成纤维细胞分化，以及（iv）抑制关键的功能后果 驱动成纤维细胞转化为肌成纤维细胞的内在能力的调节蛋白。