Exosome therapy for acute stroke with large artery occlusion

外泌体治疗急性中风伴大动脉闭塞

基本信息

批准号：
10335192
负责人：
ZHENG GANG ZHANG
金额：
$ 39.53万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10335192
关键词：
Acute Adjuvant Adult Alteplase Blood - brain barrier anatomy Brain hemorrhage Cell Adhesion Molecules Cell Therapy Cells Cerebrovascular Circulation Cerebrovascular system Cerebrum Clinical Data Development Endothelial Cells Extravasation FDA approved Genes Goals Human Infarction Intercellular adhesion molecule 1 Ischemia Ischemic Stroke Knock-out Lead Life Lipids Mediating MicroRNAs Middle Cerebral Artery Occlusion Modeling Molecular Nervous System Physiology Neurological outcome Outcome Patients Perfusion Play Proteins RNA Rattus Reperfusion Therapy Role Signal Transduction Stroke Testing Therapeutic Therapeutic Effect Thrombectomy Thromboplastin Thrombosis Tissues Toll-like receptors Treatment Efficacy acute stroke aged artery occlusion base blood-brain barrier disruption brain endothelial cell exosome experience gene network improved intercellular communication middle age nano-exosomes nanovesicle neurovascular injury novel therapeutics standard of care success therapy development thrombogenesis thrombolysis thrombotic vascular injury

项目摘要

Abstract: Large cerebral vessel occlusion is the most disabling and life-threatening form of ischemic stroke. Human stroke primarily occurs in late middle age and beyond. Approximately two thirds eligible patients treated with tPA experience incomplete reperfusion. Thrombectomy is now also a standard of care for treatment of acute stroke with large vessel occlusion. However, recanalization of the occluded large vessels by thrombectomy only leads to ~71% of patients achieving improved tissue reperfusion, often incomplete. In addition, due to unfavorably large ischemic cores, many patients with large artery occlusion are not eligible to receive tPA or thrombectomy. Patients with reperfusion of the ischemic tissue are closely associated with good clinical outcome. Thus, there is a compelling need to develop therapies in combination with tPA and thrombectomy to enhance cerebral perfusion and thereby augment the therapeutic efficacy of tPA and thrombectomy monotherapies. Also, therapies to block ischemic core expansion will increase numbers of patients who would be eligible to receive tPA and thrombectomy. Using rat models of embolic middle cerebral artery occlusion (eMCAO) and transient MCAO (tMCAO, ischemia/reperfusion), we found that exosomes derived from cerebral endothelial cells (CEC- exos) in combination with tPA after eMCAO or CEC-exos given upon reperfusion after tMCAO substantially increased recanalization and downstream cerebral blood flow (CBF), and reduced blood brain barrier (BBB) leakage and infarction compared to tPA or tMCAO alone. Exosomes are nano-vesicles that contain lipids, proteins, and RNAs including microRNAs (miRs). Our preliminary data suggest that exosomal cargo miRs likely contribute to the therapeutic effect of CEC-exos in combination with tPA on acute stroke by acting on cerebral endothelial cells to suppress proteins that promote thrombosis and BBB disruption. We thus propose to develop CEC-exo therapy as an adjunctive treatment to enhance tPA and thrombectomy treatments of acute ischemic stroke. Aim 1 is to investigate whether the CEC-exo therapy as an adjunctive treatment enhances tPA and thrombectomy treatments in aged rats after large artery occlusion. Aim 2 is to investigate whether CEC exosomal cargo miRs contribute to CEC-exos-amplified thrombolysis leading to reduction of neurovascular damage. Aim 3 investigates whether a special set of CEC-exo cargo miRs contribute to the therapeutic effect CEC-exos on stroke- induced neurovascular damage by suppressing a network of pro-BBB leakage and thrombotic genes. Accomplishing these aims will potentially lead to development of a mechanistically based exosome therapy as an adjunctive treatment to enhance tPA and thrombectomy treatments of acute ischemic stroke, leading to improvement in the neurological outcome.

抽象的：大脑血管阻塞是缺血性中风的最残疾和威胁生命的形式。人类中风主要发生在中年晚期及以后。大约三分之二的符合条件的患者用TPA经验不完整的再灌注。血栓切除术现在也是护理的标准用大容器阻塞治疗急性中风。但是，封闭大容器的重新定性血栓切除术仅导致约71％的患者获得改善的组织再灌注，这通常不完整。在此外，由于不利的脑缺血核心，许多大动脉闭塞的患者没有资格接受TPA或血栓切除术。缺血组织再灌注的患者与良好的临床结果。因此，迫切需要与TPA结合使用疗法血栓切除术以增强脑灌注，从而增强TPA的治疗功效血栓切除术单层。同样，阻断缺血性核心扩张的疗法将增加数量有资格接受TPA和血栓切除术的患者。使用栓塞中大脑的大鼠模型动脉闭塞（EMCAO）和瞬态MCAO（TMCAO，缺血/再灌注），我们发现外泌体在EMCAO或CEC-EXOS之后衍生自脑内皮细胞（CEC- EXOS）与TPA结合 TMCAO后再灌注后给予重新续签和下游大脑血液与单独使用TPA或TMCAO相比，流动（CBF）以及血脑屏障（BBB）泄漏和梗死减少。外泌体是含有脂质，蛋白质和RNA（包括microRNAS（miRS））的纳米叶子。我们的初步数据表明，外泌体货物MIR可能有助于CEC-EXOS在通过作用在脑部内皮细胞上抑制蛋白质，与TPA结合在急性中风上促进血栓形成和BBB破坏。因此，我们建议将CEC-EXO治疗作为辅助治疗治疗以增强急性缺血性中风的TPA和血栓切除术治疗。目标1是调查 CEC-EXO治疗作为辅助治疗是否可以增强TPA和血栓切除术治疗大动脉阻塞后老化的大鼠。 AIM 2是研究CEC CEC是否外泌体货物mirs 有助于CEC-EXOS扩增的溶栓，从而减少神经血管损伤。目标3 研究一组特殊的CEC-EXO货物MIR是否有助于治疗效应CEC-EXOS对中风诱导的神经血管损伤通过抑制pro-BBB泄漏和血小板基因网络。实现这些目标将有可能导致基于机械的外部体的发展治疗是一种辅助治疗，以增强急性缺血性中风的TPA和血栓切除术治疗，导致神经系统结局的改善。