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

基本信息

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
项目类别：
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

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

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项目摘要

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).

概括：缺血性中风是美国死亡和长期残疾的主要原因。当前的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恢复血流随重新定性的。但是，很大一部分损坏是由缺血/再灌注引起的，发生在再灌注阶段：缺血组织IS 从回流早期开始，迅速产生了重氧，活性氧（ROS）。事实证明，再灌注损伤很难治疗药物，可能是因为有效的药物在再灌注的早期阶段，浓度尚未充分积累。线粒体电子传输链（ETC）是细胞期间ROS产生的主要部位由于ET的高激活而引起的压力，这会导致高线粒体膜电位（∆ψm），这反过来触发了过多的ROS产生。我们建议理想的疗法应针对 ETC非侵入性可防止ROS从回流的发作中产生。根据我们在此应用程序中的总体目标是开发一种新的非侵入性疗法以正常化电流期间的线粒体多动症。我们将利用感光性近红外光（NIR）的细胞色素C氧化酶（COX）的特性调节线粒体活性，从而减弱ROS的产生，因此限制了大脑中的缺血/再灌注损伤。细胞色素C氧化酶是主要的细胞光照片 NIR的受体和终端酶。我们发现了特定的NIR 部分抑制Cox的波长（而不是激活Cox，即当前的范例）。我们表明，在再灌注时应用的抑制性NIR提供了深刻的神经保护。在此提案中，我们将以这些引人入胜的初步数据为基础利用我们的研究团队独特的多学科专业知识来： •询问缺血/再灌注损伤和NIR治疗的分子基础（目标1）。 •揭示中风后NIR治疗的机制（AIM 2） •开发NIR疗法作为缺血性中风的治疗方法（AIM 3）。