A Novel Intervention for Cerebral Ischemia

项目摘要/摘要 中风是美国成年人长期残疾的主要原因，目前还没有治疗方法 预防中风引起的神经缺陷。神经发生是重要的内源性机制之一。 用于中风后神经元的替代、修复和功能恢复。然而，大多数新产生的 中风后不久，大脑中的神经元就会死亡。在可能促进可行的神经元替代的机制中， 具有适当的血管生成和新生血管的良好的神经血管生态位是最关键的。 因此，同时促进神经发生和血管生成的策略将大大改善神经元。 中风后的置换和神经康复。 烟酰胺磷酸核糖转移酶(NAMPT)已被证明具有神经保护作用。 缺血性脑损伤。NAMPT显著促进细胞增殖、迁移和毛细血管样管形成 在人脐静脉内皮细胞培养中。然而，NAMPT在血管生成方面的作用 对脑缺血的研究还不够深入。此外，NAMPT是否会增加神经发生仍然存在 未知。我们最近发现，除了急性神经保护外，NAMPT还促进大脑修复和 神经血管重塑。令人惊讶的是，我们发现NAMPT重组蛋白可以通过血脑 并改善抗脑缺血的长期功能结果。因此， 本项目的目的是测试NAMPT的新的神经保护/神经恢复功能 NAMPT治疗脑缺血，长期目标是开发NAMPT作为一种新的临床相关治疗药物 治疗缺血性中风。需要检验的假设是NAMPT可以预防缺血性脑损伤和 通过促进血管生成和神经再生来改善长期的神经学结果。焦点 用大脑中动脉闭塞(MCAO)诱导小鼠脑缺血，模拟脑缺血的病理生理过程 临床缺血性卒中后脑组织的变化。提出了以下具体目标： 目的1：验证NAMPT减少脑损伤和改善长期神经功能的假设 局灶性脑缺血后的预后。NAMPT对缺血性脑损伤Will的神经保护作用 首先在转基因小鼠身上进行测试，这些转基因小鼠特定地在大脑中过度表达NAMPT，然后再将其翻译成 将使用重组NAMPT蛋白进一步测试治疗缺血性中风的潜力。这个 评估的终点包括梗死面积和功能结果。 目的2：验证NAMPT治疗促进脑神经血管重塑的假说， 包括脑缺血后血管生成和神经再生的增强。重组人的作用 NAMPT蛋白对卒中后梗塞周围脑区新生血管的影响将被定量分析。这个 NAMPT对神经干细胞增殖、迁移、分化及神经元替代的影响 还将检查缺血性中风。 拟议工作与退伍军人管理局病人护理任务的相关性 每年约有11,000名退伍军人因新中风住院，多达80,000名退伍军人 中风幸存者。中风后肢体残疾的人口继续增长，因为缺乏 有效的治疗方法限制和/或修复中风后毁灭性的神经元损伤。拟议的研究将 开发NAMPT作为一种新的、临床可行的治疗策略，以提供急性神经保护以及 中风后的长期神经康复。这项研究的成功将促进中风后的康复 并提高中风退伍军人的生活质量。

Project Summary/Abstract Stroke is the leading cause of long-term disability in adults in the United States, and no therapy is available to prevent stroke-induced neurological deficits. Neurogenesis is one of the important endogenous mechanisms for neuronal replacement, repair and functional recovery after stroke. However, the majority of newly generated neurons in the brain die soon after stroke. Among the mechanisms that could foster viable neuronal replacement, a favorable neurovascular niche with proper angiogenesis and neovascularization is the most crucial one. Therefore, strategies to enhance both neurogenesis and angiogenesis would greatly improve neuronal replacement and neurological recovery after stroke. Nicotinamide phosphoribosyltransferase (NAMPT) has been proven to be neuroprotective against ischemic brain injury. NAMPT markedly promotes cell proliferation, migration and capillary-like tube formation in human umbilical vein endothelial cell cultures. However, the effect of NAMPT on angiogenesis in the context of cerebral ischemia is under-explored. Furthermore, whether NAMPT increases neurogenesis remains unknown. We have recently found that besides acute neuroprotection, NAMPT also promotes brain repair and neurovascular remodeling. Strikingly, we found that NAMPT recombinant protein can cross the blood brain barrier (BBB) and also improve long-term functional outcomes against cerebral ischemia. Therefore, the objective of this project is to test the novel neuroprotective/ neurorestorative function of NAMPT in the context of cerebral ischemia with a long-term aim to develop NAMPT as a novel, clinically relevant therapeutic agent for ischemic stroke. The hypothesis to be tested is that NAMPT protects against ischemic brain injury and improves long-term neurological outcomes by enhancing angiogenesis and neurogenesis. Focal ischemia will be induced in mice by middle cerebral artery occlusion (MCAO) to mimic the pathophysiological changes in the brain after clinical ischemic stroke. The following specific aims are proposed: Aim 1: Test the hypothesis that NAMPT reduces brain damage and improves long-term neurological outcomes after focal cerebral ischemia. The neuroprotective effect of NAMPT on ischemic brain injury will be first tested in transgenic mice that overexpress NAMPT specifically in the brain, and then its translational potential for the treatment of ischemic stroke will be further tested using recombinant NAMPT protein. The endpoints for assessment include infarct size and functional outcomes. Aim 2: Test the hypothesis that NAMPT treatment enhances cerebral neurovascular remodeling, including augmented angiogenesis and neurogenesis after cerebral ischemia. The effect of recombinant NAMPT protein on post-stroke neovascularization in peri-infarct brain areas will be quantitatively analyzed. The effect of NAMPT on neural stem cell proliferation, migration, differentiation and neuronal replacement following ischemic stroke will also be examined. Relevance of the proposed work to the VA patient care mission Approximately 11,000 veterans are hospitalized annually with new strokes and up to 80,000 veterans are stroke survivors. The population with post-stroke physical disability continues to grow due to the lack of effective therapies to restrict and/or repair devastating neuronal damage after stroke. The proposed study will develop NAMPT as a novel, clinically feasible therapeutic strategy to offer acute neuroprotection as well as long-term neurological recovery after stroke. The success of this study will enhance post-stroke rehabilitation and improve quality of life for veterans suffering from stroke.