Non-invasive mitochondrial modulation therapy for ischemic stroke

缺血性中风的非侵入性线粒体调节疗法

• 批准号: 10583532
• 负责人: MAIK HUETTEMANN
• 金额: $ 47.32万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583532
• 关键词: Algorithms; Animal Model; Attenuated; Basic Science; Binding Sites; Blood flow; Brain; Brain Injuries; Brain Ischemia; Cause of Death; Cells; Cellular Stress; Cerebrum; Clinical; Data; Development; Electron Transport; Enzymes; Free Radical Formation; Free Radicals; Future; Generations; Goals; Histologic; Hour; Hyperactivity; Interruption; Intervention; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Knock-out; Laboratories; Light; Macrophage; Magnetic Resonance Imaging; Mediating; Membrane Potentials; Metabolic; Middle Cerebral Artery Occlusion; Mitochondria; Modeling; Modification; Molecular; Molecular Target; Morbidity - disease rate; Mus; Neuroglia; Neurologic; Obstruction; Oxidases; Oxygen; Parkin; Patients; Penetration; Peripheral; Pharmaceutical Preparations; Phase; Phosphorylation; Phototherapy; Process; Production; Property; Protocols documentation; Quality Control; Rattus; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Reporter; Research; Starvation; Stress; Stroke; Technology; Testing; Therapeutic; Therapeutic Uses; Time; Tissue Model; Tissues; Transgenic Mice; Translations; attenuation; clinical implementation; cytochrome c oxidase; disability; in vivo; innovation; mitochondrial membrane; mortality; mouse model; multidisciplinary; neuroinflammation; neuroprotection; neurovascular injury; neurovascular unit; novel; pharmacologic; prevent; programs; rational design; restoration; standard care; standard of care; stroke model; stroke therapy; therapy design

Summary: Ischemic stroke is a leading cause of death and long-term disability in the US. The current gold standard for the treatment of ischemia-reperfusion injury in the setting of focal brain ischemia is restoration of blood flow with recanalization. However, a substantial portion of the damage caused by ischemia/reperfusion occurs during the reperfusion phase: as ischemic tissue is reoxygenated, reactive oxygen species (ROS) are quickly generated, starting early during reflow. Reperfusion injury has proved difficult to treat pharmacologically, likely because effective drug concentrations have not built up sufficiently during the early phase of reperfusion. The mitochondrial electron transport chain (ETC) is a major site of ROS production during cellular stress due to ETC hyper-activation, which causes high mitochondrial membrane potentials (∆Ψm), which in turn trigger excessive ROS production. We propose that the ideal therapy should target the ETC non-invasively to prevent the generation of ROS from the onset of reflow. Accordingly, our overall goal in this application is to develop a new, non-invasive therapy to normalize mitochondrial hyperactivity during reflow. We will capitalize on the photoreceptive properties of cytochrome c oxidase (COX) for near infrared light (NIR) to modulate mitochondrial activity, thereby attenuating the production of ROS and, as a result, limit ischemia/reperfusion injury in the brain. Cytochrome c oxidase is the primary cellular photo- acceptor of NIR and the terminal enzyme of the ETC. We have discovered specific NIR wavelengths that partially inhibit COX (instead of activating COX, i.e., the current paradigm). We show that inhibitory NIR, applied at the time of reperfusion, provides profound neuroprotection. In this proposal, we will build on these compelling preliminary data and capitalize on the unique, multi-disciplinary expertise of our research team to: • Interrogate the molecular underpinnings of ischemia/reperfusion injury and of NIR therapy (Aim 1). • Uncover the mechanisms of NIR therapy following stroke (Aim 2) • Develop the optimal use of NIR therapy as a treatment for ischemic stroke (Aim 3).

总结： 缺血性卒中是美国死亡和长期残疾的主要原因。目前黄金 在局灶性脑缺血的情况下治疗缺血-再灌注损伤的标准是 通过再通恢复血流。然而，很大一部分的损失 由缺血/再灌注引起的缺血/再灌注损伤发生在再灌注阶段：由于缺血组织 在再充氧的情况下，活性氧物质（ROS）快速产生，在回流期间早期开始。 再灌注损伤已被证明难以治疗，可能是因为有效的药物 在再灌注的早期阶段，浓度没有充分积累。 线粒体电子传递链（ETC）是细胞内ROS产生的主要场所。 由于ETC过度活化而引起的应激，其导致高线粒体膜电位（线粒体膜电位）， 这反过来又引发了过量的ROS产生。我们认为理想的治疗应该针对 ETC非侵入性地防止再流开始时ROS的产生。因此，委员会认为， 我们在这项应用中的总体目标是开发一种新的非侵入性治疗方法， 再流时线粒体活性亢进。我们将利用感光细胞 细胞色素c氧化酶（考克斯）对近红外光（NIR）的调节特性 线粒体活性，从而减弱ROS的产生，并因此限制 脑缺血/再灌注损伤。细胞色素c氧化酶是主要的细胞光- 近红外受体和ETC的末端酶，我们发现了特异性的近红外 部分抑制考克斯（而不是激活考克斯，即，目前的模式）。 我们发现，在再灌注时应用抑制性NIR， 神经保护在本提案中，我们将以这些令人信服的初步数据为基础， 利用我们研究团队独特的多学科专业知识： ·探究缺血/再灌注损伤和NIR治疗的分子基础 (Aim 1）。 ·揭示中风后近红外治疗的机制（目标2） ·开发NIR疗法作为缺血性卒中治疗的最佳用途（目标3）。