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 该申请寻求资金来支持NIAMS K08收件人在过渡到研究期间 独立。广泛的目标是研究线粒体损伤相关分子的作用 软骨损伤和创伤后骨关节炎（PTOA）发生后的模式（MDAMP）。 在许多组织中，损伤诱导的线粒体功能障碍会导致细胞释放MDAMP 细胞外环境，可永久注射并导致持续的组织损伤。最近的工作， 在申请人的K08奖上进行的表明，线粒体功能障碍是急性反应 软骨损伤的软骨细胞，重要的是，米特罗维治疗可防止细胞死亡和软骨 退化。但是，线粒体功能障碍导致PTOA的基本机制不好 理解的齿和mdamps尚未在软骨中研究。测试MDAMP释放的假设 来自受伤引起的线粒体功能障碍的软骨细胞，这些损伤信号为 与临床关节创伤相关，我们将在四个不同模型系统中测量MDAMP。 AIM 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 使用已知在其他细胞类型中诱导MDAMP释放的几种刺激性的刺激性。抑制剂 线粒体功能障碍和线粒体也将通过阻断MDAMP释放的能力进行测试。接下来，我们 将确定软骨外植体的机械损伤是否导致MDAMP释放在体内。 AIM 1的结果 将提供有关如何触发MDAMP释放以及如何进行热对其进行操作的洞察力。 AIM 2将分析马滑液中的MDAMP，以确定关节损伤是否导致MDAMP释放 体内。 MDAMP浓度将在以前的研究中的银行滑液中测量，其中马 发生了实验性关节损伤，有或没有关节内有线保护疗法。确定MDAMP是否 释放与自然发生的疾病有关，MDAMP将以从 急性关节创伤的临床患者。 AIM 2的结果将确定米属保护是否可以防止MDAMP 在体内释放，如果滑动流体MDAMP是早期软骨/骨损伤的有用指标。 该建议是建立在申请人的K08研究的基础上的，并利用了这些研究中产生的样本， 允许在2年的时间范围内完成拟议的目标。这些研究代表了一条新线 调查，独立于申请人的心理。 Delco博士仅产生了研究概念，设计了 实验，撰写建议，并将负责项目监督。通过建立一个新区域 该领域的研究，该奖项将使Delco博士能够建立独立的研究计划并继续 开发骨关节炎和再生医学中线粒体生物学的利基。了解角色 MDAMP的近期潜力可以改变我们诊断和治疗关节损伤的方式。