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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：
8623156
负责人：
Rona G Giffard
金额：
$ 34.04万
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/8623156
关键词：
Acute Address Adult Aftercare Apoptosis Area Behavioral 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 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 brain cell burden of illness compare effectiveness cost cytokine dentate gyrus deprivation disability effective therapy functional outcomes improved in vivo inhibitor/antagonist macrophage nerve stem cell neural precursor cell neurobehavioral neuroblast neurogenesis neuronal survival novel strategies overexpression post stroke public health relevance repaired response response to injury stroke recovery stroke therapy

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）：中风是美国第三大最常见的死亡原因，也是慢性神经功能障碍的主要原因，造成大量医疗保健支出。超过100种以神经元存活为目标的中风潜在疗法在临床试验中失败。迫切需要开发在初始缺血事件后有效且优选针对多种机制的潜在治疗方法。实验性缺血触发脑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随后迁移到受损区域。然而，这些细胞的存活率很低，部分原因是周围的促炎环境。损失的