Translational Technologies for Ameliorating Brain Injury

改善脑损伤的转化技术

• 批准号: 9765382
• 负责人: Sujatha Kannan
• 金额: $ 51.49万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-16 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765382
• 关键词: Acute; Animal Model; Anti-inflammatory; Antiinflammatory Effect; Area; Arousal; Astrocytes; Attenuated; Behavioral; Biodistribution; Biological Markers; Brain; Brain Injuries; Brain region; Cardiopulmonary Resuscitation; Chronic; Clinical Research; Cognitive; Coma; Cysteine; Dendrimers; Electroencephalography; Electrophysiology (science); Entropy; Female; Frequencies; Future; Gender; Goals; Half-Life; Heart Arrest; Hippocampus (Brain); Hypothalamic structure; Inflammation; Inflammatory Response; Injury; Intranasal Administration; Investigation; Ischemia; Lead; Learning; Long-Term Effects; Measures; Mediating; Memory; Microglia; Modeling; Monitor; Nervous System Trauma; Neurologic; Neurological outcome; Neuropeptides; Outcome; Oxidative Stress; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Perfusion; Property; Rattus; Recovery; Research; Resuscitation; Rodent Model; Signal Transduction; Site; Sleep; Structure; Technology; Testing; Therapeutic; Therapeutic Effect; Wakefulness; Work; attenuation; base; behavior test; behavioral outcome; clinical application; clinical translation; clinically translatable; combinatorial; depressive symptoms; excitotoxicity; experimental study; glial activation; improved; improved outcome; inflammatory marker; male; nanotherapy; natural hypothermia; neurobehavior; neurobehavioral; neuroinflammation; neuron apoptosis; neurophysiology; neuroprotection; novel; orexin A; response; targeted delivery; targeted treatment; translational approach; uptake

Abstract Cardiac arrest (CA) has devastating consequences to survival and, even after successful resuscitation brain injury can be quite severe. The broad goal of our research is to develop translational, therapeutic technologies for mitigating brain injury from global ischemia following CA. One prevailing solution is therapeutic hypothermia (TH). While TH has been shown to improve outcome, it does not promote arousal or reduce neuro- inflammation. We now propose a novel and potentially translational delivery approach to promote arousal by intranasal delivery of ORXA. In addition, we also focus on examining the intrinsic bio-distribution and anti- inflammatory properties of dendrimers in a chronic long-term survival after CA. We propose discovery experiments that, we hope to show, will lead to clinically translatable solutions. This proposal is founded on exciting preliminary results. We have discovered an approach to targeting the orexinergic pathway through the delivery of Orexin-A (ORXA). This idea is supported by our preliminary studies that first showed that intra-cerebral ventricle (ICV) ORXA treatment reduces inflammation, and in addition, rapidly enhances arousal. This idea is further validated by our novel quantitative EEG (qEEG) monitoring technology. We have observed brain injury and poor outcome due to neuro-inflammation post-CA brain injury. In our preliminary studies, we found that uptake of dendrimers, specifically Dendrimer- N-acetyl cysteine (D- NAC), occurs at injured brain regions. We have shown that dendrimers serve as a targeted therapeutic technology for neuro-inflammation by attenuating neuro-inflammation, oxidative stress and excitotoxicity. Further, we extend our work to long term observations and set up gender-specific models. For the proposed investigations, we will utilize extensively researched and validated rodent model of CA and resuscitation, propose both acute and chronic experimentation in male and female subjects and carry out the monitoring of systemic perfusion, electrophysiological (qEEG) monitoring, comprehensive behavioral examination, and histopathological analysis. Our overarching hypothesis is that intranasal ORXA will initiate brain arousal effects and early anti-inflammatory response, while dendrimer nanotherapy, D-NAC, will reduce chronic neuro-inflammation; and together, these therapies will improve long term survival. The specific aims of this project are to: Aim 1: Determine the therapeutic effects of intranasal ORXA treatment on early neurophysiological recovery, cognitive and behavioral outcome following post-CA coma. Aim 2: Determine the window of anti-inflammatory therapeutic effects of intranasal ORXA applied immediately post-resuscitation. Aim 3: Demonstrate that treatment with dendrimer nanotherapy using dendrimer conjugated to N-acetyl-L- cysteine (D-NAC), increases survival, improves neurobehavior and reduces chronic neuro-inflammation, after resuscitation. Aim 4: Achieve early arousal and neuroprotective effect from post-CA neuroinflamation by sequentially using of intranasal ORXA and D-NAC for sustained neuroprotection leading to improved long term neurological outcomes and survival post-CA. There are very limited current therapeutic solutions for improving survival and cognitive outcome after global ischemia resulting from CA. Our dual approaches, intranasal ORXA delivery and dendrimer mediated targeting, serve the unmet needs of promoting arousal, and mitigating post-CA neuro-inflammation for patients. Further, the intranasal delivery approach, once validated, should be amenable to rapid clinical translation. Overall, our research lays the groundwork for future clinical studies directed at improving the patient outcome after resuscitation.

抽象的 心脏骤停（CA）对生存产生毁灭性后果，即使成功复苏大脑 受伤可能很严重。我们研究的广泛目标是开发翻译，治疗技术 用于减轻脑部缺血后的脑损伤。一种盛行的解决方案是治疗性体温过低 （th）。虽然已显示出可以改善结果，但并不能促进唤醒或减少神经 - 炎。现在，我们提出了一种新颖的，潜在的转化传递方法，以促进唤醒 ORXA的鼻内输送。此外，我们还专注于检查内在的生物分布和抗 在大约之后，树枝状聚合物在慢性长期存活中的炎症特性。我们提出了发现 我们希望表明的实验将导致可翻译的解决方案。 该建议建立在令人兴奋的初步结果上。我们发现了一种针对的方法 通过递送Orexin-A（ORXA）的OREXIN能途径。这个想法得到了我们的初步研究的支持 首先表明脑内心室（ICV）ORXA治疗可减少炎症，此外，迅速 增强唤醒。我们新颖的定量脑电图（QEEG）监视进一步验证了这个想法 技术。我们已经观察到CA脑损伤后神经炎症引起的脑损伤和不良预后。 在我们的初步研究中，我们发现对树突聚合物的摄取，特别是树突聚合物 - n-乙酰半胱氨酸（D- NAC），发生在受伤的大脑区域。我们已经证明树枝状聚合物充当靶向治疗 通过减弱神经炎症，氧化应激和 兴奋性毒性。此外，我们将工作扩展到长期观察并建立特定于性别的模型。 对于拟议的调查，我们将利用经过广泛研究和验证的CA的啮齿动物模型 复苏，提出男性和女性受试者的急性和慢性实验，并进行 监测系统性灌注，电生理（QEEG）监测，全面行为 检查和组织病理学分析。 我们的总体假设是鼻内ORXA会引发脑唤醒作用和早期抗炎 反应，而树突聚合物纳米疗法D-NAC将减少慢性神经炎症。在一起，这些 疗法将改善长期生存。该项目的具体目的是： 目标1：确定鼻内ORXA治疗对早期神经生理恢复的治疗作用， CA后昏迷后的认知和行为结果。 目标2：确定立即应用鼻内ORXA的抗炎治疗效应的窗口 后震动。 AIM 3：证明使用与N-乙酰L-结合的树突聚合物进行树突聚合物纳米疗法的治疗 半胱氨酸（D-NAC）增加生存率，改善神经行为并减少慢性神经炎症，之后 复苏。 AIM 4：通过顺序使用CA后神经发作的早期唤醒和神经保护作用 鼻内ORXA和D-NAC的持续神经保护，导致长期神经学改善 结局和生存后。 当前的治疗解决方案非常有限，用于改善全球生存和认知结果 由Ca产生的缺血。我们的双重方法，鼻内ORXA的递送和树枝状聚合物介导的靶向， 满足了促进唤醒的需求，并减轻患者的CA后神经炎症后的需求。更远， 一旦验证，鼻内递送方法应适合快速临床翻译。总体而言，我们的 研究为未来的临床研究奠定了基础，该研究旨在改善患者的结果 复苏。