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

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：缺血性中风是美国目前死亡和长期残疾的主要原因。局灶性脑缺血时缺血再灌注损伤的治疗标准是通过再通恢复血流然而，很大一部分损伤。由缺血/再灌注引起的发生在再灌注阶段：因为缺血组织是再氧化的活性氧 (ROS) 会在回流焊过程早期迅速产生。再灌注损伤已被证明很难通过药物治疗，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建立。线粒体电子传递链（ETC）是细胞内ROS产生的主要场所。由于 ETC 过度激活而产生的压力，导致线粒体膜电位升高 (ΔΨm)，这反过来会引发过量的 ROS 产生，我们建议理想的治疗应该针对这一点。 ETC 非侵入性地防止回流焊开始时产生 ROS。我们在此应用中的总体目标是开发一种新的非侵入性疗法来使回流期间线粒体过度活跃我们将利用光感受器。细胞色素 C 氧化酶 (COX) 的近红外光 (NIR) 调节特性线粒体活性，从而减弱 ROS 的产生，从而限制细胞色素 C 氧化酶是大脑缺血/再灌注损伤的主要细胞光损伤。 NIR的受体和ETC的末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，即当前范例）。我们表明，在再灌注时应用抑制性近红外可以提供深远的影响。在这项提案中，我们将基于这些令人信服的初步数据和利用我们研究团队独特的多学科专业知识来： • 探究缺血/再灌注损伤和近红外治疗的分子基础（目标 1）。 • 揭示中风后近红外治疗的机制（目标 2） • 开发NIR 疗法作为缺血性中风治疗的最佳用途（目标3）。