Mitoprotective therapy for treatment of ankle PTOA

项目摘要摘要 创伤后骨关节炎(PTOA)常继发于关节损伤，有临床表现。 疼痛和功能障碍在受伤后几个月到几年后才会出现。目前还没有有效的治疗方法来预防或减缓 PTOA进展，有证据表明，必须在受伤后立即进行干预，以改变疾病 当然了。新肽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 治疗几种疾病的试验。该项目将检验以下假设：急性机械创伤 诱导软骨细胞MT功能障碍导致PTOA，并用SS-31恢复MT生物能量学 会在体内阻止PTOA的发展。第一，软骨早期(几秒到几天)的时间反应 将评估MT功能、细胞死亡和基质降解方面的损伤，以确定治疗方法 治疗软骨机械性损伤后MT功能障碍的时间窗。然后，SS-31的疗效 在减轻软骨损伤的影响方面，将进行研究，以确定丝裂保护可以 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，它的影响 线粒体在体内对PTOA的稳定性将在以下的过急性到慢性期进行评估 体内冲击性软骨损伤和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细胞凋亡，以及 抑制软骨退变的进展，从而提供预防PTOA的第一种治疗方法。全 这项提案的组成部分反映并支持了国家关节炎和癌症研究所的使命 肌肉骨骼和皮肤病。拟议项目的完成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的急性损伤后病理生物学是至关重要的，因为它代表了一个时间点， 在疾病完全确定之前，有可能采取旨在预防PTOA的干预措施。这个 SS-31在几个已经确定疾病的II期临床试验中的成功表明， 线粒体膜保护也将是治疗PTOA的一种有效方法。 诊断和治疗。两名博士生将接受这项提议的培训，培训内容来自多方面的 从人类临床和动物模型角度出发的跨学科科学家和临床医生团队。 最后，本提案中所有组建的团队成员在国内和国际上都有很好的代表性 在各自的领域中，他们致力于传播科学知识，并具有丰富的经验 会议和期刊出版物上的信息。为这个项目组建的跨学科团队已经 建立了协作关系，并带来了各自的当代概念和技术 将信息转化为现实的人类临床应用，以预防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.