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 关节纤维化是常规总膝关节置换术的一种非常普遍的衰弱并发症。我们的实验室 制定基于机制的策略（i）治疗关节纤维化的治疗，（ii）疾病的早期干预 启动过程，（iii）识别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一个主要的知识差距 关节纤维化是通过与炎症相关组织修复过程的局部改变在体内启动的 联合手术后。我们建议炎症过程调节机械保护的形成 瞬态结缔组织以及对正常关节组织愈合的管制导致 （原始）肌纤维细胞的生长，分化和活性可能从周围出现 滑膜组织的室。 要了解导致关节纤维化的机制，我们将分析（i）（i） 兔模型中的炎症过程（AIM 1）； （ii）机制 在关节纤维化期间通过活检和原发性分子分析在关节纤维化过程中失控的肌纤维细胞生成 接受修订TKA的患者的细胞培养物，以及建立的体外模型 培养中的肌纤维细胞增殖和分化，以及与参与的肥大细胞的共培养模型 组织修复期间的初始炎症反应（AIM 2）。 该提案的关键可交付成果是通过（i）机械化来建立转化创新（目标1） 炎症在关节纤维化和（ii）抗炎药的潜在功效的表征 减轻或逆转疾病进展。此外，这项研究在概念上是创新的（AIM 2） 建立（III）细胞结构连接的激酶介导的信号通路和基因调节网络 介导关节组织中的肌纤维细胞分化，以及（iv）抑制钥匙的功能后果 促进成纤维细胞转化为肌纤维细胞的内在能力的调节蛋白。