Mitochondrial protection in post-stroke recovery

中风后恢复中的线粒体保护

基本信息

批准号：
9005885
负责人：
Rona G Giffard
金额：
$ 34.39万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9005885
关键词：
Acute Address Adult Aftercare Apoptosis Area Brain Cause of Death Cell Culture Techniques Cell Death Cell Density Cell Proliferation Cell Survival Cells Chronic Clinical Trials Conditioned Culture Media Development Event Exposure to Failure Generations Genetic Glucose Goals Health Health Expenditures Impairment In Vitro Inflammation Inflammatory Inflammatory Response Injury Ischemia Lead Link Microglia Middle Cerebral Artery Occlusion Mission Mitochondria Modeling Molecular Mus Neuroglia Neurologic Neurons Outcome Oxygen Recovery Research Role SOD2 gene Stroke Testing Thiamine Thymidine Kinase Tissues Translations United States Work behavioral outcome brain cell burden of illness compare effectiveness cost cytokine dentate gyrus deprivation disability effective therapy functional outcomes improved improved outcome in vivo inhibitor/antagonist macrophage nerve stem cell neural precursor cell neurobehavioral neuroblast neurogenesis neuronal survival novel strategies overexpression post stroke repaired response response to injury stroke recovery stroke therapy survival outcome

项目摘要

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.

描述（由申请人提供）：中风是美国第三大常见的死亡原因，也是美国慢性神经残疾的主要原因，导致了大量的医疗保健支出。在临床试验中，靶向神经元存活的中风生存期的100多种潜在疗法失败。迫切需要迫切需要开发潜在的疗法，并在易血症发生事件后有效，最好靶向多种机制。实验性缺血会触发脑室和齿状回生发区中神经发生的增加。这些内源性神经前体细胞然后迁移到损害区域。然而，这些细胞的存活很低，部分原因是周围的促炎环境。损失未成熟的神经元和炎症最近被公认为恢复的障碍。因此，改善新产生的神经元生存并调节缺血后炎症反应的策略是改善中风结果的有前途的方法。线粒体是缺血性损伤的主要靶标。先前的工作表明，未成熟的双果蛋白+神经元特别容易受到线粒体损害的影响，并且对线粒体功能的保护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/小胶质细胞激活的关键决定因素。该提案将使用遗传和药理学方法的线粒体保护方法，以增加对线粒体在损伤反应和内源性修复中的作用的了解。未成熟神经元对甚至轻度线粒体损伤的极端敏感性将在AIM 1中通过选择性靶向线粒体保护，以靶向未成熟的双胞质神经元。线粒体保护对缺血性损伤或炎症神经元存活的影响将在体外评估。在小鼠中风模型中，将评估神经元的分化和长期生存率，以及神经行为结局。 AIM 2选择性地研究了小胶质细胞的线粒体保护，并评估对小胶质细胞炎症反应和神经发生的影响。神经前体的分化命运和存活都受周围的神经胶质细胞的调节，促炎激活的小胶质细胞强烈抑制神经发生。由于小胶质细胞激活是通过线粒体功能调节的，因此将评估小胶质细胞活化对分化和存活的影响新神经元在体外的影响，并将评估体内中风后。 AIM 3研究了缺血后可以给予的潜在线粒体保护策略。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果的影响。保护线粒体可能会直接改善新的神经元存活，并且对小胶质细胞对缺血的反应可能会导致组织较高的组织增强，神经发生增加并改善了长期神经行为结果。线粒体在缺血后恢复中的作用是一个新领域，具有识别的重要潜力新颖的方法来增强中风恢复。