Mechanotransduction in Meniscus Health and Repair

半月板健康和修复中的机械传导

• 批准号: 10322100
• 负责人: Amy L McNulty
• 金额: $ 41.37万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322100
• 关键词: ADAMTS; Anabolism; Biochemical; Biological; Biological Models; Biomechanics; Calcium; Calcium Signaling; Cartilage; Catabolism; Cell Proliferation; Cell physiology; Cells; Chemicals; Clinical; Collagen; Cyclic AMP; Degenerative polyarthritis; Development; Dinoprostone; Disease; Equilibrium; Exercise; Extracellular Matrix; Family suidae; Gene Expression; Goals; Health; Human; Immobilization; Immunohistochemistry; In Vitro; Inflammatory; Inflammatory Response; Intercellular Fluid; Interleukin-1; Joints; Knee; Lead; MAP Kinase Gene; Matrix Metalloproteinases; Mechanical Stimulation; Mechanics; Mediating; Mediator of activation protein; Meniscus structure of joint; Metabolic; Metabolism; Modeling; Operative Surgical Procedures; Oryctolagus cuniculus; Pain; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Play; Process; Role; Sepharose; Signal Pathway; Signal Transduction; Surgical sutures; Testing; Tissue Engineering; Tissues; Translating; United States; Vanilloid; Western Blotting; Work; cell motility; cytokine; disability; experience; fluid flow; inhibitor; joint injury; joint loading; mechanical load; mechanical properties; mechanical signal; mechanotransduction; meniscal tear; meniscus injury; monolayer; new therapeutic target; prevent; protein expression; receptor; repair model; repaired; response; shear stress; tissue regeneration; tissue repair; transcriptome sequencing

ABSTRACT. Meniscal injuries are a significant clinical problem as each year 850,000 meniscal surgeries are performed in the United States and nearly twice as many worldwide. Meniscal tears in the avascular inner zone of the tissue do not heal well with suturing or conservative treatments and can ultimately lead to the development of osteoarthritis (OA). Therefore, new strategies are needed to enhance endogenous meniscus repair and tissue regeneration. The menisci play a critical biomechanical role in the knee, providing load support, joint stability, and congruity. Meniscus tissue is maintained through a balance of anabolic and catabolic activities of meniscus cells. These cellular activities are controlled not only by biochemical factors in the joint but also by physical factors associated with joint loading. Mechanobiology, which is the influence of mechanical factors on the biologic response of cells, is important in converting physical signals into metabolic and inflammatory responses in meniscus. However, the mechanisms by which mechanical signals are transduced in meniscus cells have yet to be identified. Our overall goal is to identify critical meniscus mechanotransduction pathways and modulate these pathways to promote meniscus repair and prevent OA development. Our work has shown that transient receptor potential vanilloid 4 (TRPV4) is a critical component in cartilage mechanotransduction and metabolism. The activation of TRPV4 can block IL-1 induced catabolic responses and also increases cell migration and proliferation, which are important processes to enhance tissue repair. While we have found that TRPV4 is expressed in the meniscus, the function of this mediator in meniscus health and disease is currently unknown. In this proposal, we will determine how mechanotransduction occurs through TRPV4 in meniscus and identify modulators of this pathway that will be used to enhance tissue repair and prevent OA development. We hypothesize that mechanotransduction by TRPV4 plays a key role in meniscus metabolism and can be modulated to enhance meniscus repair and prevent the development of OA. In this proposal, we will determine the effects of mechanical stimulation on TRPV4-mediated metabolism in healthy meniscus cells. Next, we will elucidate alterations in TRPV4-mediated mechanotransduction pathways in meniscus pathology. Finally, we will enhance integrative meniscus repair and prevent the development of OA by modulation of mechanotransduction pathways. In this proposal, we will identify the key signaling pathways downstream of TRPV4 that may function as novel drug targets to 1) treat patients with immobilized joints to simulate exercise and maintain joint health; 2) enhance meniscus tissue regeneration using tissue engineering strategies; and 3) enhance meniscus repair and prevent the development of OA. Novel therapeutic targets identified in this proposal can subsequently be developed into drugs to enhance meniscus repair and prevent the development of OA.

抽象的。 半月板损伤是一个重大的临床问题，因为在美国，每年有85万例半月板手术。 在美国，这一数字几乎是全球的两倍。犬组织无血管内区半月板撕裂 缝合或保守治疗不能很好地愈合，最终可能导致骨关节炎的发展 (办公自动化)。因此，需要新的策略来促进内源性半月板修复和组织再生。 半月板在膝关节中起着至关重要的生物力学作用，提供负荷支持、关节稳定性和协调性。 半月板组织是通过半月板细胞的合成代谢和分解代谢活动的平衡来维持的。这些 细胞活动不仅受关节中的生化因素控制，还受相关的物理因素控制。 用联合加载。机械生物学，即机械因素对细胞生物反应的影响， 在半月板中将物理信号转化为代谢和炎症反应很重要。然而， 机械信号在半月板细胞中传递的机制尚未确定。我们的 总的目标是确定关键的半月板机械转导通路并调节这些通路 促进半月板修复和防止骨性关节炎发展的途径。 我们的工作表明，瞬时受体电位香草素4(TRPV4)是软骨中的一个关键成分 机械转导和代谢。激活TRPV4可阻断IL-1诱导的分解代谢反应 也会增加细胞的迁移和增殖，这是加强组织修复的重要过程。而当 我们已经发现TRPV4在半月板中表达，该介质在半月板健康中的作用以及 疾病目前尚不清楚。在这项提案中，我们将确定机械转导是如何通过 半月板中的TRPV4，并确定这一途径的调节物，将用于促进组织修复和预防 办公自动化的发展。我们推测TRPV4的机械转导在半月板新陈代谢中起关键作用。 并可调节以促进半月板修复，防止骨性关节炎的发展。在这项提案中，我们将 确定机械刺激对健康半月板细胞中TRPV4介导的代谢的影响。 接下来，我们将阐明半月板病理中TRPV4介导的机械转导通路的变化。 加强半月板的整体性修复，通过调控半月板的功能，防止骨性关节炎的发生。 机械转导途径。在这项提案中，我们将确定关键的信号通路下游 TRPV4可能作为新的药物靶点用于1)治疗关节僵硬的患者模拟运动 并保持关节健康；2)使用组织工程策略增强半月板组织再生；以及3) 加强半月板修复，防止骨性关节炎的发展。本研究确定了新的治疗靶点 建议随后可开发成药物，以加强半月板修复和防止发展 对于办公自动化来说。