The role of mitochondrial Damage Associated Molecular Patterns (mDAMPs) in posttraumatic osteoarthritis.

线粒体损伤相关分子模式 (mDAMP) 在创伤后骨关节炎中的作用。

• 批准号: 9810990
• 负责人: Michelle Lee Delco
• 金额: $ 7.85万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-08 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9810990
• 关键词: Acute; Applications Grants; Area; Arthritis; Arthroscopy; Award; Biological Assay; Biological Markers; Biological Models; Biology; Bone Injury; Cardiolipins; Cartilage; Cartilage injury; Cell Death; Cells; Cessation of life; Chondrocytes; Clinical; Culture Media; Data; Degenerative polyarthritis; Development; Devices; Diagnosis; Diagnostic radiologic examination; Disease; Environment; Enzyme-Linked Immunosorbent Assay; Equus caballus; Freezing; Functional disorder; Funding; Future; Goals; Grant; Harvest; Human; Immunologics; In Vitro; Inflammation; Inflammatory; Injury; Interleukin-1 beta; Joints; Lesion; Link; Liquid substance; Measures; Mechanics; Mediator of activation protein; Mentors; Microscopic; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Modeling; Molecular; Molecular Analysis; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Nucleic Acids; Oligomycins; Outcome Measure; Pain; Palliative Care; Pathology; Patients; Pattern; Peptides; Pharmaceutical Preparations; Pharmacology; Phospholipids; Process; Proteins; Regenerative Medicine; Research; Role; Rotenone; Sampling; Sclerosis; Secondary to; Signal Transduction; Sirolimus; Stimulus; Stress; Surface; Synovial Fluid; Synovial Membrane; Talus; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Traumatic injury; United States National Institutes of Health; Work; bone; candidate marker; cartilage degradation; cell type; clinical biomarkers; cytochrome c; design; effective therapy; experimental study; extracellular; in vivo; inhibitor/antagonist; injured; insight; joint inflammation; joint injury; mitochondrial dysfunction; novel; novel diagnostics; preservation; prevent; programs; response; response to injury

PROJECT SUMMARY/ABSTRACT This application seeks funding to support a NIAMS K08 recipient during her transition to research independence. The broad objective is to investigate the role of mitochondrial Damage-Associated Molecular Patterns (mDAMPs) after cartilage injury and in the development of posttraumatic osteoarthritis (PTOA). In many tissues, injury-induced mitochondrial dysfunction causes cells to release mDAMPs into the extracellular environment, which perpetuates inflammation and leads to ongoing tissue damage. Recent work, performed during the applicant’s K08 award, demonstrated that mitochondrial dysfunction is an acute response of chondrocytes to cartilage injury, and importantly, mitoprotective therapy prevents cell death and cartilage degeneration. However, the basic mechanisms whereby mitochondrial dysfunction leads to PTOA are not well understood, and mDAMPs have not been studied in cartilage. To test the hypothesis that mDAMPs are released from chondrocytes undergoing injury-induced mitochondrial dysfunction, and that these damage signals are associated with clinical joint trauma, we will measure mDAMPs in four different model systems. The goal of Aim 1 is to identify specific signals that initiate mDAMP release. First, chondrocytes will be stressed in vitro using several stimuli known to induce mDAMP release in other cell types. Inhibitors of mitochondrial dysfunction and mitophagy will also be tested for their ability to block mDAMP release. Next, we will determine if mechanical injury to cartilage explants results in mDAMP release ex vivo. The results of Aim 1 will provide insight into how mDAMP release is triggered, and how it may be manipulated therapeutically. Aim 2 will analyze mDAMPs in equine synovial fluid to determine if articular injury results in mDAMP release in vivo. mDAMP concentration will be measured in banked synovial fluid from previous studies, where horses had experimental joint injury, with and without intraarticular mitoprotective therapy. To determine if mDAMP release is associated with naturally occurring disease, mDAMPs will be measured in equine synovial fluid from clinical patients with acute joint trauma. Results of Aim 2 will determine if mitoprotection can prevent mDAMP release in vivo, and if synovial fluid mDAMPs are useful indicators of early cartilage/bone injury. This proposal builds on the applicant’s K08 research, and utilizes samples generated during those studies, allowing the proposed aims to be accomplish within the 2-year time frame. These studies represent a new line of inquiry, independent from the applicant’s mentor. Dr. Delco solely generated the research concept, designed the experiments, wrote the proposal, and will be responsible for project oversight. By establishing a new area of research within the field, this award will allow Dr. Delco to build an independent research program and continue to develop a niche in mitochondrial biology in osteoarthritis and regenerative medicine. Understanding the role of mDAMPs has the near-term potential to change the way we diagnose and treat joint injury.

项目摘要/摘要 此应用程序寻求资金，以支持NIAMS K08获奖者在过渡到研究期间 独立。广泛的目标是研究线粒体损伤相关分子的作用 在软骨损伤后和创伤后骨关节炎(PTOA)的发展过程中。 在许多组织中，损伤诱导的线粒体功能障碍导致细胞将mDAMPs释放到 细胞外环境，使炎症持续存在，并导致持续的组织损伤。最近的工作， 在申请人的K08奖期间进行的，证明线粒体功能障碍是一种急性反应 软骨细胞对软骨损伤的影响，重要的是，有丝分裂保护治疗可以防止细胞死亡和软骨形成 退化。然而，线粒体功能障碍导致PTOA的基本机制尚不清楚。 了解到，mDAMPs还没有在软骨中进行研究。要检验mDAMP被释放的假设 来自经历损伤诱导的线粒体功能障碍的软骨细胞，这些损伤信号是 结合临床关节创伤，我们将在四个不同的模型系统中测量mDAMPs。 目标1的目标是确定启动mDAMP释放的特定信号。首先，软骨细胞将是 在体外使用几种已知可诱导其他类型细胞释放mDAMP的刺激。抗肿瘤药物 线粒体功能障碍和有丝分裂也将测试它们阻止mDAMP释放的能力。接下来，我们 将确定软骨移植的机械损伤是否会导致mDAMP在体外释放。AIM 1的结果 将深入了解mDAMP释放是如何触发的，以及它可能是如何在治疗方面被操纵的。 AIM 2将分析马关节液中的mDAMP，以确定关节损伤是否导致mDAMP释放 在活体内。MDAMP浓度将在先前研究中储存的滑液中测量，其中马 有实验性关节损伤，接受和不接受关节内线粒体保护治疗。要确定mDAMP是否 释放与自然发生的疾病有关，mDAMPs将在马的滑液中进行测量 临床上有急性关节创伤的患者。AIM 2的结果将确定线粒体保护是否可以预防mDAMP 如果关节液mDAMPs在体内释放，mDAMPs是早期软骨/骨损伤的有用指标。 该建议建立在申请人的K08研究的基础上，并利用了在这些研究期间产生的样本， 以便在两年的时间框架内实现拟议的目标。这些研究代表了一条新的路线 调查，独立于申请人的导师。Delco博士独自产生了研究概念，设计了 提案写道，这些实验将负责项目监督。通过建立一个新的领域 在该领域的研究，该奖项将允许Delco博士建立独立的研究计划并继续 在骨关节炎和再生医学中开拓线粒体生物学的利基市场。了解角色 可能在短期内改变我们诊断和治疗关节损伤的方式。