A Novel Intervention for Cerebral Ischemia

脑缺血的新干预措施

• 批准号: 8633630
• 负责人: GUODONG CAO
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633630
• 关键词: Acute; Adult; Anabolism; Area; Blood - brain barrier anatomy; Blood capillaries; Brain; Brain Injuries; C57BL/6 Mouse; Cell Culture Techniques; Cell Death Induction; Cell Proliferation; Cerebral Ischemia; Cerebrum; Clinical; Drug Delivery Systems; Endothelial Cells; Fostering; Generations; Human; Infarction; Intervention; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Lead; Link; Middle Cerebral Artery Occlusion; Mission; Mus; Nerve; Neurologic; Neurological outcome; Neurons; Patient Care; Pharmaceutical Preparations; Population; Production; Proteins; Quality of life; Recombinant Proteins; Recombinants; Recovery of Function; Reporting; Source; Stroke; Stroke prevention; Survivors; System; Testing; Therapeutic; Therapeutic Agents; Transgenic Mice; Tube; Umbilical vein; United States; Veterans; Work; angiogenesis; brain repair; capillary; clinically relevant; disability; effective therapy; enzyme biosynthesis; functional improvement; functional outcomes; improved; in vivo; migration; neovascularization; nerve stem cell; neurogenesis; neurological recovery; neuronal replacement; neuroprotection; neurorestoration; nicotinamide phosphoribosyltransferase; novel; overexpression; post stroke; public health relevance; repaired; stroke rehabilitation; success

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.

项目总结/摘要 中风是美国成年人长期残疾的主要原因， 预防中风引起的神经功能缺损。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 脑中的神经元在中风后很快死亡。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血管形成的有利的神经血管生态位是最关键的一个。 因此，增强神经发生和血管生成的策略将极大地改善神经元的生长。 脑卒中后的神经功能恢复。 烟酰胺磷酸核糖基转移酶（NAMPT）已被证明是神经保护， 缺血性脑损伤NAMPT可显著促进细胞增殖、迁移和毛细血管样管形成 在人脐静脉内皮细胞培养物中。然而，NAMPT对血管生成的影响在这种情况下， 脑缺血的研究还不充分。此外，NAMPT是否增加神经发生仍有待研究。 未知我们最近发现，除了急性神经保护，NAMPT还促进大脑修复， 神经血管重塑引人注目的是，我们发现NAMPT重组蛋白可以穿过血脑 屏障（BBB），并改善对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， 长期目标是将NAMPT开发为一种新型的临床相关治疗药物 缺血性中风待检验的假设是NAMPT可防止缺血性脑损伤， 通过增强血管生成和神经发生来改善长期神经系统结果。焦 通过大脑中动脉闭塞（MCAO）在小鼠中诱导缺血以模拟病理生理学 临床缺血性中风后大脑的变化。建议的具体目标如下： 目标1：检验NAMPT可减少脑损伤并改善长期神经功能的假设 局灶性脑缺血后的结局。NAMPT对缺血性脑损伤的神经保护作用 首先在大脑中特异性过表达NAMPT的转基因小鼠中进行测试，然后将其翻译成 将使用重组NAMPT蛋白进一步测试治疗缺血性中风的潜力。的 用于评估的终点包括梗死面积和功能结果。 目的2：检验NAMPT治疗增强脑神经血管重塑的假设， 包括脑缺血后增加的血管生成和神经发生。重组的影响 将定量分析NAMPT蛋白对梗死周围脑区卒中后新血管形成的影响。的 NAMPT对神经干细胞增殖、迁移、分化和神经元替代影响 还将检查缺血性中风。 拟定工作与VA患者护理使命的相关性 每年约有11，000名退伍军人因新发中风住院， 中风幸存者中风后身体残疾的人口继续增长，由于缺乏 限制和/或修复中风后破坏性神经元损伤的有效疗法。拟定的研究将 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 中风后的长期神经恢复。这项研究的成功将促进中风后康复 并改善中风老兵的生活质量。