Engineering cartilage mechanotransduction for treatment of chondrocyte injury

工程软骨机械传导治疗软骨细胞损伤

• 批准号: 8622225
• 负责人: WOLFGANG B. LIEDTKE
• 金额: $ 20.72万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8622225
• 关键词: Address; Adopted; Affect; Age; Age-Years; Applications Grants; Arthritis; Biochemical; Biological; Biological Markers; Biology; Biomechanics; Body Weight; Cartilage; Cartilage injury; Cells; Cellular Mechanotransduction; Chondrocytes; Degenerative polyarthritis; Disease; Elderly; Elements; Engineering; Equilibrium; Etiology; Event; Family suidae; Friction; Functional disorder; Gait; Grant; Histology; Incidence; Injury; Ion Channel; Joints; Knowledge; Lead; Life; Mechanical Stress; Mechanics; Mediating; Metabolic; Modeling; Molecular; Morphology; Mus; Obesity; Pain; Pathogenesis; Pathologic; Pathology; Peptides; Physical environment; Physiological; Play; Population; Preparation; Prevalence; Property; Public Health; Reading; Research; Role; Signal Transduction; Spiders; Sports; Surface; Tarantula Venoms; Therapeutic; Time; Toxin; Traumatic Arthropathy; United States; articular cartilage; base; clinically relevant; economic impact; gait examination; high risk; human disease; in vivo; inhibitor/antagonist; injured; innovation; insight; joint injury; joint loading; novel; prevent; protective effect; public health relevance; research study; response; response to injury; skeletal

Engineering cartilage mechanotransduction for treatment of chondrocyte injury Abstract Osteoarthritis (OA) is a painful and debilitating disease of the synovial joints, affecting an estimated 12% of the total United States population 25-74 years of age. The prevalence of this disease increases significantly with age, with radiographic evidence observed in over 70% of the population over age 65. OA research is important, considering the extensive impact and public health consequences of this disease. The etiology of OA is not fully understood, and there exist no disease-modifying therapies. OA is distinctively characterized by the progressive, degenerative changes in the morphology, composition, and mechanical properties of articular cartilage, indicating that the normal balance of metabolic activities in chondrocytes, the cellular element that makes and maintains all cartilage, has been severely disrupted. While the relationships between the biochemical and biomechanical events involved in this pathology are not yet known, it is now evident that mechanical factors play a critical role in the sequence of events leading to the metabolic imbalance of cartilage in OA. The over-riding objective of this study is to deconstruct mechanosensitive signaling in primary chondrocytes to provide better understanding of a basic mechanism of enormous relevance, and also to provide critical insight to enhance more rational therapies of joint-loading-induced injuries including OA. We have made an exciting discovery of expression of PIEZO mechanosensitive channels in chondrocytes, which appear functional in response to mechanical loading. Thus, the Specific Aims of this grant are: (1) To examine the role of PIEZO channels in controlling the anabolic and catabolic response to physiologic and excessive mechanical loading using an organotypic preparation of cartilage. (2) In a mouse post-injury arthritis model, to apply the Piezo antagonist GsMTx4 to the affected joint as a means of preventing chondrocyte-mediated joint degeneration. Aim 1 will be in a porcine model and take advantage of the spider toxin GsMTx4, which blocks Piezo channels. Aim 2 will take advantage of a post-traumatic arthritis model that we have adopted to mice, with a read-out of gait change and joint histology. Based on our exciting discovery, addressing these Aims will increase our insights into OA pathophysiology in a non-incremental way, and directly guide us towards new specific therapies.

工程化软骨机械转导治疗软骨细胞损伤 摘要 骨关节炎(OA)是一种疼痛和衰弱的滑膜关节疾病，估计影响12%的滑膜关节 美国总人口年龄在25-74岁之间。这种疾病的患病率随着 年龄，在超过70%的65岁以上人口中观察到放射证据。办公自动化研究是 重要的是，考虑到这种疾病的广泛影响和公共卫生后果。该病的病因学 目前对骨性关节炎的认识还不完全，也不存在治疗疾病的方法。办公自动化的显著特点是 关节退行性改变关节的形态、成分和力学性能的进行性退行性变化 软骨，表明软骨细胞代谢活动的正常平衡，这是 制造和维护所有的软骨，已经被严重破坏。而两国之间的关系 参与这种病理的生化和生物力学事件尚不清楚，现在很明显 机械因素在导致软骨代谢失衡的一系列事件中起着关键作用 在办公自动化中。 这项研究的首要目标是解构原代软骨细胞中的机械敏感信号，以 提供对具有巨大相关性的基本机制的更好理解，并提供批判性见解 加强包括骨性关节炎在内的关节负荷性损伤的合理治疗。我们取得了令人振奋的成就 在软骨细胞中发现了压电机械敏感通道的表达，该通道在软骨细胞中具有功能 对机械载荷的响应。因此，这项拨款的具体目的是：(1)研究压电体的作用 控制生理和过度机械负荷下合成代谢和分解代谢反应的通道 使用一种器官类型的软骨制剂。(2)在小鼠损伤后关节炎模型上，应用Piezo 拮抗剂GsMTx4可作为预防软骨细胞介导的关节退变的手段。 Aim 1将在猪模型中利用蜘蛛毒素GsMTx4，它可以阻断Piezo通道。 Aim 2将利用我们在小鼠身上采用的创伤后关节炎模型，读出 步态变化和关节组织学。基于我们令人兴奋的发现，解决这些目标将增加我们的 以非增量的方式深入了解OA的病理生理学，并直接引导我们走向新的特定领域 治疗。