Mechanotransduction in Meniscus Health and Repair

半月板健康和修复中的机械传导

基本信息

批准号：
10091311
负责人：
Amy L McNulty
金额：
$ 40.51万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10091311
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/antagonist joint injury joint loading mechanical load mechanical properties 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

项目摘要

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要的临床问题，因为每年有 850,000 例半月板手术在美国的数量几乎是全球的两倍。组织内无血管区域的半月板撕裂会造成缝合或保守治疗不能很好地治愈，最终可能导致骨关节炎的发展（办公自动化）。因此，需要新的策略来增强内源性半月板修复和组织再生。半月板在膝关节中发挥着关键的生物力学作用，提供负载支撑、关节稳定性和一致性。半月板组织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。这些细胞活动不仅受到关节中的生化因素的控制，还受到相关物理因素的控制。联合加载。力学生物学，即机械因素对细胞生物反应的影响，对于将物理信号转化为半月板的代谢和炎症反应非常重要。然而，半月板细胞中机械信号转导的机制尚未确定。我们的总体目标是确定关键的半月板机械传导途径并调节这些途径促进半月板修复和预防 OA 发展的途径。我们的工作表明瞬时受体电位香草酸 4 (TRPV4) 是软骨的关键成分力传导和代谢。 TRPV4 的激活可以阻断 IL-1 诱导的分解代谢反应还增加细胞迁移和增殖，这是增强组织修复的重要过程。尽管我们发现TRPV4在半月板中表达，该介质在半月板健康中的功能以及疾病目前未知。在本提案中，我们将确定力传导如何通过半月板中的 TRPV4 并确定该途径的调节剂，该调节剂将用于增强组织修复和预防 OA开发。我们假设 TRPV4 的机械传导在半月板代谢中发挥关键作用并可进行调节以增强半月板修复并预防 OA 的发展。在本提案中，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学中 TRPV4 介导的机械转导途径的改变。最后，我们将通过调节半月板的综合修复来预防 OA 的发展。力传导途径。在本提案中，我们将确定下游的关键信号通路 TRPV4 可作为新型药物靶点，用于 1) 治疗关节固定的患者以模拟运动并保持关节健康； 2）利用组织工程策略增强半月板组织再生；和 3) 增强半月板修复并预防 OA 的发展。本研究中确定的新治疗靶点该提案随后可以开发成药物，以增强半月板修复并预防发展 OA。