Translational Technologies for Ameliorating Brain Injury

改善脑损伤的转化技术

基本信息

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
项目类别：
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

项目摘要

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) 对生存造成毁灭性后果，即使在成功进行脑复苏后伤害可能相当严重。我们研究的总体目标是开发转化治疗技术用于减轻 CA 后全身缺血引起的脑损伤。一种流行的解决方案是治疗性低温（TH）。虽然 TH 已被证明可以改善结果，但它不会促进唤醒或减少神经炎。我们现在提出了一种新颖且潜在的转化传递方法来促进唤醒 ORXA 的鼻内递送。此外，我们还重点研究内在的生物分布和抗- CA 后慢性长期生存中树枝状聚合物的炎症特性。我们提出发现我们希望展示的实验将带来可临床转化的解决方案。该提案基于令人兴奋的初步结果。我们发现了一种针对目标的方法通过递送食欲素-A (ORXA) 的食欲素能途径。这个想法得到了我们的初步研究的支持首先表明脑室内 (ICV) ORXA 治疗可减轻炎症，此外，还能迅速增强觉醒。我们新颖的定量脑电图（qEEG）监测进一步验证了这个想法技术。我们观察到 CA 脑损伤后神经炎症导致脑损伤和不良预后。在我们的初步研究中，我们发现树枝状聚合物的摄取，特别是树枝状聚合物-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大分子可以作为靶向治疗药物通过减轻神经炎症、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针对特定性别的模型。对于拟议的研究，我们将利用经过广泛研究和验证的 CA 啮齿动物模型和复苏，建议在男性和女性受试者中进行急性和慢性实验，并进行全身灌注监测、电生理（qEEG）监测、综合行为学检查和组织病理学分析。我们的首要假设是鼻内 ORXA 将引发大脑唤醒作用和早期抗炎作用反应，而树枝状聚合物纳米疗法 D-NAC 将减少慢性神经炎症；一起，这些治疗将改善长期生存。该项目的具体目标是：目标 1：确定鼻内 ORXA 治疗对早期神经生理恢复的治疗效果， CA 昏迷后的认知和行为结果。目标 2：确定立即应用鼻内 ORXA 的抗炎治疗效果窗口复苏后。目标 3：证明使用与 N-乙酰基-L-缀合的树枝状聚合物纳米疗法进行治疗半胱氨酸（D-NAC），增加存活率，改善神经行为并减少慢性神经炎症，复苏。目标 4：通过序贯使用，实现 CA 后神经炎症的早期唤醒和神经保护作用鼻内 ORXA 和 D-NAC 提供持续的神经保护，从而改善长期神经功能 CA 后的结果和生存。在全球范围内改善生存和认知结果的当前治疗解决方案非常有限 CA引起的缺血。我们的双重方法，鼻内 ORXA 递送和树枝状大分子介导的靶向，满足患者促进唤醒和减轻 CA 后神经炎症的未满足需求。更远，鼻内给药方法一旦经过验证，应该能够快速临床转化。总体而言，我们的研究为未来旨在改善患者治疗效果的临床研究奠定了基础复苏。