CEREBRAL PROTECTION & RECOVERY AFTER CIRCULATORY ARREST

大脑保护

• 批准号: 6736193
• 负责人: YAN XU
• 金额: $ 32.9万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6736193
• 关键词: NMDA receptors; angiogenesis; brain derived neurotrophic factor; cerebral ischemia /hypoxia; gene therapy; heart arrest; immunocytochemistry; laboratory rat; magnetic resonance imaging; neurogenesis; neurons; neuroprotectants; neuropsychological tests; nonhuman therapy evaluation; nuclear magnetic resonance spectroscopy; vascular endothelial growth factors

DESCRIPTION (provided by applicant): This is competitive renewal of R01NS/HL36124-06, which has supported the development and continuation of the primary project in the Principal Investigator's laboratory. The investigators have developed and validated a clinically relevant outcome model of cardiac arrest and resuscitation in rats. The model is fully compatible with the use of the state-of-the-art magnetic resonance imaging (MRI) in order to (1) correlate long-term neuronal damage with post-resuscitation abnormalities in regional cerebral blood flow (rCBF), ion/water homeostasis as manifested in apparent diffusion coefficient (ADC), and cerebral energy metabolism, and (2) to evaluate the efficacy of different treatment strategies for cerebral protection and resuscitation after a well-controlled circulatory arrest. Research in the past four years has led to the conclusion that treatment based on energy metabolism and excitotoxicity mechanisms will inevitably fail if the vascular response to global ischemia and re-oxygenation is not addressed. For the next five years, the investigators will test the central hypothesis that intravascular goodness after resuscitation can be restored by intraparenchymal interventions. The research will focus on two closely related intraparenchymal events: angiogenesis and neurogenesis. Possible roles of the brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) in alleviation of reperfusion injury wilt be investigated. BDNF and VEGF are chosen for their proven neuroprotective effects against ischerrfia, but their direct involvement in providing intraparenchymal treatment for reperfusion injury and protracted hypoperfusion has not been explored. The mechanisms of their protection against reperfusion injury are not fully understood. The synergistic link between these two factors, which underlies their choice for this project, is the recent finding that both factors seem to exert their neuroprotective effects via the extmcellular signal-related protein kinase (ERK) pathway. Methods for widespread gene delivery and transfer into the brain parenehyma have been developed by the investigators. The proposed new studies will combine gene therapy using recombinant adeno-associated viruses (rAAV) and stern cell therapy to accomplish the following three specific aims: Specific Aim #1: To investigate the therapeutic effects of the wide-spread over-expression of BDNF on the regional reperfusion recovery and reduction of neuronal loss in the selective vulnerability regions. Specific Aim #2: To achieve wide-spread gene delivery and over-expression of the main splice variants of VEGF (VEGF121 and VEGF165) in the rat brain to assist the post-resuscitation angiogenesis against hypoperfusion. Specific Aim #3: To devise a method for diffusive cerebral transplantation of multipotent stem cells and, in combination with BDNF and VEGF gene therapy, to study interaction of angiogenesis and neurogenesis. It is hoped that these specific investigations wilt pave the way to ultimately identifying the causal interaction between angiogenesis and neurogenesis after resuscitation from global ischemia.

描述（由申请人提供）： 这是R 01 NS/HL 36124 -06的竞争性更新，支持主要研究者实验室主要项目的开发和继续。研究人员已经开发并验证了大鼠心脏骤停和复苏的临床相关结果模型。该模型与最先进的磁共振成像（MRI）的使用完全兼容，以便（1）将长期神经元损伤与局部脑血流（rCBF）、如表观扩散系数（ADC）所示的离子/水稳态和脑能量代谢中的复苏后异常相关联，（2）评价不同治疗策略对控制良好的停循环后脑保护和复苏的效果。过去四年的研究得出的结论是，如果不解决血管对全脑缺血和再氧合的反应，基于能量代谢和兴奋性毒性机制的治疗将不可避免地失败。在接下来的五年里，研究人员将检验这一中心假设，即复苏后血管内的良好状态可以通过脑实质内干预恢复。这项研究将集中在两个密切相关的实质内事件：血管生成和神经发生。脑源性神经营养因子（BDNF）和血管内皮生长因子（VEGF）在减轻再灌注损伤中的可能作用有待进一步研究。选择BDNF和VEGF是因为它们已被证明对ischerrfia具有神经保护作用，但它们直接参与提供再灌注损伤和长期低灌注的实质内治疗尚未被探索。其抗再灌注损伤的机制尚未完全清楚。这两个因素之间的协同联系，这是他们选择这个项目的基础，是最近的发现，这两个因素似乎通过细胞外信号相关蛋白激酶（ERK）途径发挥其神经保护作用。研究人员已经开发出了广泛的基因递送和转移到大脑parenehyma的方法。拟议的新研究将结合联合收割机基因治疗，使用重组腺相关病毒（rAAV）和干细胞治疗，以实现以下三个具体目标：具体目标#1：调查广泛过度表达的BDNF对局部再灌注恢复和减少选择性脆弱区域神经元损失的治疗效果。具体目标#2：目的：实现VEGF主要剪接体（VEGF 121和VEGF 165）在大鼠脑内的广泛基因递送和过表达，以辅助复苏后血管生成对抗低灌注。具体目标#3：目的建立多能干细胞脑内移植的方法，并结合BDNF和VEGF基因治疗，研究血管生成和神经发生的相互作用。希望这些具体的研究能够为最终确定全脑缺血复苏后血管生成和神经发生之间的因果相互作用铺平道路。