Mitochondrial protection in post-stroke recovery

描述（由申请人提供）：中风是美国第三大最常见的死亡原因，也是慢性神经系统残疾的主要原因，导致大量的医疗保健支出。超过100种针对脑卒中神经元存活的潜在疗法在临床试验中失败。目前迫切需要开发在初始缺血事件后有效且优选靶向多种机制的潜在疗法。实验性缺血触发室下和齿状回生发区神经发生增加。这些内源性神经前体细胞然后迁移到损伤区域。然而，这些细胞的存活率很低，部分原因是周围的促炎环境。损失 不成熟的神经元和炎症最近被认为是恢复的障碍。因此，改善新生神经元存活和调节缺血后炎症反应的策略是改善卒中结局的有希望的方法。线粒体是缺血性损伤的主要靶点。先前的工作表明，未成熟的Doublecortin+神经元特别容易受到线粒体损伤的影响，并且保护线粒体功能可以在体外和体内挽救神经发生。最近的证据还表明，线粒体功能是促炎性巨噬细胞/小胶质细胞活化的关键决定因素。线粒体保护的遗传学和药理学方法将用于本提案中，以增加对线粒体在损伤反应和内源性修复中的作用的理解。未成熟神经元对甚至轻度线粒体损伤的极端敏感性将在目标1中通过选择性靶向线粒体保护未成熟的Doublecortin表达神经元来解决。将在体外评估线粒体保护对缺血性损伤或炎症的神经元存活的影响。将在小鼠中风模型中评估神经元的分化和长期存活以及神经行为结果。目的2研究选择性靶向线粒体对小胶质细胞的保护作用，并评价其对小胶质细胞炎症反应和神经发生的影响。神经前体细胞的分化命运和存活都受到周围胶质细胞的调节，并且促炎激活的小胶质细胞强烈抑制神经发生。由于小胶质细胞活化受线粒体功能调节，因此将评价改变的小胶质细胞活化对体外和体内卒中后新神经元的分化和存活的影响。目的3研究缺血后可能的线粒体保护策略。将评估损伤后线粒体靶向保护对神经发生、长期神经元存活和功能结局的影响。保护线粒体可能直接改善新神经元存活，并且改变小胶质细胞对缺血的反应可能导致增强的组织保留、增加的神经发生和改善的长期神经行为结果。线粒体在缺血后恢复中的作用是一个新的领域，具有重要的识别潜力。 促进中风恢复的新方法。

DESCRIPTION (provided by applicant): Stroke is the third most common cause of death, and the leading cause of chronic neurological disability in the United States, causing substantial health-care expenditures. More than 100 potential therapies for stroke targeting neuronal survival have failed in clinical trials. Development of potential therapies effective after the iniial ischemic event and preferably targeting multiple mechanisms is urgently needed. Experimental ischemia triggers increased neurogenesis in the subventricular and dentate gyrus germinal zones. These endogenous neural precursor cells then migrate to areas of damage. However, the survival of these cells is low, in part due to the surrounding pro-inflammatory milieu. Loss of immature neurons and inflammation are recently recognized roadblocks to recovery. Strategies to improve survival of newly generated neurons and modulate the post-ischemic inflammatory response are thus promising approaches to improve stroke outcome. Mitochondria are primary targets of ischemic injury. Previous work demonstrated that immature Doublecortin+ neurons are particularly vulnerable to mitochondrial impairment, and that protection of mitochondrial function can rescue neurogenesis both in vitro and in vivo. Recent evidence also suggests that mitochondrial function is a key determinant of pro-inflammatory macrophage/microglial activation. Genetic and pharmacological approaches to mitochondrial protection will be used in this proposal to increase understanding of the role of mitochondria in injury response and endogenous repair. The extreme sensitivity of immature neurons to even mild mitochondrial impairment will be addressed in Aim 1 by selectively targeting mitochondrial protection to immature Doublecortin expressing neurons. The effect of mitochondrial protection on neuronal survival of ischemic injury or inflammation will be assessed in vitro. Differentiation and long ter survival of neurons, and neurobehavioral outcome will be assessed in a mouse stroke model. Aim 2 investigates selectively targeting mitochondrial protection to microglia and evaluates the effect on the microglial inflammatory response and on neurogenesis. Both the differentiation fate and survival of neural precursors are regulated by surrounding glial cells, and pro-inflammatory activated microglia strongly inhibit neurogenesis. Since microglial activation is modulated by mitochondrial function the impact of altered microglial activation on differentiation and survival f new neurons in vitro and after stroke in vivo will be evaluated. Aim 3 investigates potential mitochondrial protective strategies that can be administered after ischemia. The effect of post-injury mitochondrial targeted protection on neurogenesis, long-term neuronal survival and functional outcome will be assessed. Protecting mitochondria is likely to improve new neuron survival directly and modifying microglial response to ischemia will likely result in enhanced tissue sparing, increased neurogenesis and improved long term neurobehavioral outcome. The role of mitochondria in post-ischemic recovery is a new area with significant potential to identify novel approaches to enhance stroke recovery.