Role of prohibitin in ischemic brain injury

抑制素在缺血性脑损伤中的作用

• 批准号: 8888249
• 负责人: Ping Zhou
• 金额: $ 37.08万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8888249
• 关键词: Astrocytes; Bioenergetics; Brain; Brain Injuries; Brain Ischemia; Cell Death; Cells; Cerebral Ischemia; Cessation of life; Complex; Confocal Microscopy; Crista ampullaris; Development; Electron Microscopy; Failure; Foundations; Free Radicals; Funding; Gene Transfer; Glial Fibrillary Acidic Protein; Glucose; Hippocampus (Brain); Human; Infarction; Injury; Intervention; Ischemia; Ischemic Brain Injury; Ischemic Neuronal Injury; Ischemic Preconditioning; Ischemic Stroke; Lead; Link; Mediating; Membrane Fusion; Middle Cerebral Artery Occlusion; Mitochondria; Mitochondrial Proteins; Modeling; Morphology; Mus; Neurons; Oxygen; Phase; Predisposition; Process; Production; Prosencephalon; Proteins; Public Health; Reactive Oxygen Species; Regulation; Research; Respiratory Chain; Role; Solid; Stroke; Structure; Testing; Tetanus Helper Peptide; Tissues; Transgenic Mice; Translational Research; base; cell type; cellular targeting; deprivation; gel electrophoresis; improved; in vivo; insight; mitochondrial dysfunction; nervous system disorder; neuronal survival; neuroprotection; new therapeutic target; novel; novel strategies; novel therapeutic intervention; prohibitin; protective effect; public health relevance; targeted treatment

 DESCRIPTION (provided by applicant): Ischemic stroke remains one of the most prevalent and devastating neurological diseases for which limited treatment options are available. Therefore, new therapeutic approaches are sorely needed. Brain ischemia causes severe and often irreversible mitochondrial damage in the early phase of tissue infarction. In turn, damaged mitochondria further exacerbate brain injury by producing free radicals and promoting cell death. A mechanistic understanding of how mitochondrial function is impaired in the ischemic brain may unveil new approaches to protect mitochondria and lead to the development of new strategies for neuroprotection. We have discovered that the mitochondrial protein prohibitin (PHB) is upregulated by ischemic preconditioning and demonstrated that PHB expression by gene transfer protected cultured cortical neurons from oxygen glucose deprivation and hippocampal CA1 neurons from the delayed degeneration produced by transient forebrain ischemia in vivo. These studies clearly suggested a strong neuroprotective potential of PHB but mechanisms pertaining to the neuroprotection, especially those attributed specifically to mitochondria, need to be elucidated. For this purpose, we have developed conditional PHB transgenic (PHB-Tg) mice that express PHB selectively in neurons or astrocytes. Using these mice we propose to test the hypothesis that PHB, by regulating critical mitochondrial functions, modulates the mitochondria's susceptibility to ischemia and protects the ischemic brain from injury. In particular, we will use a model of focal cerebral ischemia produced by transient occlusion of the middle cerebral artery (MCA) to investigate whether conditional neuronal or astrocytic expression of PHB ameliorates ischemic brain injury. Furthermore, we will examine the bioenergetic mechanisms underlying mitochondrial protection by PHB, and its role in preserving mitochondrial network integrity by regulating mitochondrial fusion and fission and cristae structure in ischemic neurons. The findings of the research from the present proposal, therefore, will advance our understanding of how PHB modulates mitochondrial structure, function and dynamics, and will provide new therapeutic targets for ischemic injury based on modulating PHB expression. The findings will also advance our understanding of the fundamental processes governing neuronal survival and death through regulation of mitochondrial dynamics, and have the potential of identifying mitochondria targeted treatment strategies for other neurological diseases linked to mitochondrial dysfunction.

 描述（由适用提供）：缺血性中风仍然是有限的治疗选择有限的最普遍和毁灭性神经系统疾病之一。因此，迫切需要新的治疗方法。在组织梗死的早期，脑缺血会导致严重且通常是不可逆的线粒体损伤。反过来，通过产生自由基并促进细胞死亡，线粒体受损进一步加剧了脑损伤。对缺血性大脑中线粒体功能如何损害的机械理解可能会揭示新的方法来保护线粒体并导致新的神经保护策略的发展。我们已经发现，禁止的线粒体蛋白（PHB）是通过缺血性预处理来更新的，并证明了基因转移受到基因转移受保护的培养的皮质神经元的PHB表达，这些神经元来自氧气葡萄糖丧失和海马CA1神经元，并从跨性别前脑iSchemia Inschemia Invivo Inchemia Inschemia Inschemia Inchemia Inchemia Inchemia Inchemia Inchemia Inchemia In Invivo产生的延迟。这些研究清楚地表明，PHB具有强大的神经保护潜力，但与神经保护有关的机制，尤其是专门归因于线粒体的机制，需要阐明。为此，我们开发了有条件的PHB转基因（PHB-TG）小鼠，该小鼠在神经元或星形胶质细胞中有选择地表达PHB。使用这些小鼠，我们建议通过调节临界线粒体功能调节PHB的假设，调节线粒体机制并保护缺血性大脑免受损伤。特别是，我们将使用通过中间骨骼动脉（MCA）短暂闭塞产生的局灶性缺血模型来研究有条件的神经元或星形胶质细胞表达PHB是否可以缓解缺血性脑损伤。此外，我们将检查PHB线粒体保护的基础生物能机制，及其在缺血神经元中线粒体融合以及裂变和CRISTAE结构中通过调节线粒体网络完整性的作用。因此，本提案的研究结果将促进我们对PHB如何调节线粒体结构，功能和动力学的理解，并将为基于调节PHB表达的调节性缺血性损伤提供新的治疗靶标。这些发现还将通过调节线粒体动力学来提高我们对管理神经元生存和死亡的基本过程的理解，并有可能鉴定与线粒体功能障碍有关的其他神经系统疾病的线粒体靶向治疗策略。