Mitoprotective therapy for treatment of ankle PTOA

项目摘要 创伤后骨关节炎（PTOA）经常继发于关节损伤，具有临床表现 疼痛和功能障碍会在受伤后数月到数年内消失。没有有效的治疗方法可以预防或减缓 PTOA进展，有证据表明必须在损伤后立即进行干预以改变疾病 当然了新型肽SS-31是一种高度靶向的线粒体保护疗法，已在临床上显示出成功 用于治疗多种疾病的试验。这个项目将测试急性机械创伤 在软骨细胞中诱导MT功能障碍，导致PTOA，并用SS-31恢复MT生物能量学 将阻止体内PTOA的发展。第一，软骨的早期（数秒到数天）时间响应， 将评估MT功能、细胞死亡和基质降解方面的损伤，以鉴定治疗剂 软骨机械损伤后MT功能障碍的治疗时间窗。那么SS-31的功效 在减轻软骨损伤的影响将被研究，以确定时间过程中，线粒体保护， 有效抑制MT功能障碍，恢复细胞生物能量，防止细胞死亡。最后，影响 将在以下的急性至慢性阶段中评估体内PTOA上的线粒体稳定性： 体内撞击诱导软骨损伤和MT功能障碍。这些研究的结果将证明，如果 线粒体保护疗法恢复线粒体生物能量学，防止急性细胞损伤和凋亡， 抑制软骨退化的进展，从而提供预防PTOA的第一疗法。所有 本提案的组成部分反映并支持国家关节炎研究所的使命， 肌肉骨骼和皮肤疾病。完成拟议的项目将揭示新的科学信息 关于损伤后软骨在亚细胞到宏观分辨率尺度上的早期变化。理解 PTOA的急性损伤后病理学是关键的，因为它代表了一个时间点， 以预防PTOA为目的的干预措施在疾病完全确立之前是可能的。的 SS-31在几个已经确定疾病的II期临床试验中的成功表明， 线粒体保护也将是PTOA的有效疗法，在这些情况下，OA存在于 诊断和治疗。两名博士生将接受培训，在这个建议与投入，从多方面 跨学科的科学家和临床医生团队从人类临床和动物模型的角度。 最后，本提案中的所有团队成员在国家和国际上都有很好的代表性。 他们在各自领域的水平，并致力于和经验丰富的科学传播， 在会议和期刊出版物上提供信息。为该项目组建的跨学科团队 一个建立的合作关系，并带来了现代的概念和技术，从每个 将信息转化为现实的人类临床应用，以防止PTOA。

Project Summary Abstract Post-traumatic osteoarthritis (PTOA) frequently develops secondary to joint injury, with clinical manifestations of pain and dysfunction lagging months to years after the injury. No effective therapies exist to prevent or slow PTOA progression, and evidence indicates interventions must occur acutely after injury to modify the disease course. The novel peptide SS-31 is a highly targeted mitoprotective therapy that has shown success in clinical trials for treatment of several diseases. This project will test the hypothesis that acute mechanical trauma induces MT dysfunction in chondrocytes that leads to PTOA, and that restoring MT bioenergetics with SS-31 will arrest the development of PTOA in vivo. First, the early (seconds to days) temporal response of cartilage to injury with respect to MT function, cell death, and matrix degradation, will be assessed to identify a therapeutic window of time for treatment of MT dysfunction after mechanical injury of cartilage. Then, the efficacy of SS-31 in mitigating the effects of cartilage injury will be studied to identify the time course in which mitoprotection can effectively inhibit MT dysfunction, restore cellular bioenergetics and prevent cell death. Finally, the effects of mitochondrial stabilization on PTOA in vivo will be assessed in the peracute to chronic phases following impact-induced cartilage damage and MT dysfunction in vivo. The results of these studies will demonstrate if mitoprotective therapies restore mitochondrial bioenergetics, prevent acute cell injury and apoptosis, and inhibit the progression of cartilage degeneration, thereby providing the first therapy to prevent PTOA. All components of this proposal reflect and support the mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Completion of the proposed project will reveal novel scientific information about the early changes in cartilage at subcellular to macroscopic resolution scales after injury. Understanding the acute post-injury pathobiology of PTOA is critical because it represents a time point where true intervention, with an aim at preventing PTOA, is possible before the disease becomes fully established. The success of SS-31 in several phase II clinical trials, where disease is already established, suggests that mitoprotection will also be an effective therapy for PTOA in those cases where OA is present at the time of diagnosis and treatment. Two PhD students will be trained in this proposal with input from a multifaceted interdisciplinary team of scientists and clinicians from the human clinical and animal models perspectives. Finally, all members of the assembled team in this proposal are well represented on national and international levels in their respective fields, and they are dedicated and experienced at dissemination of scientific information at meetings and in journal publications. The interdisciplinary team assembled for this project has an established collaborative relationship and brings contemporary concepts and techniques from each respective field to translate information into a realistic human clinical application to prevent PTOA.