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(由申请人提供)：缺血性中风仍然是最普遍和破坏性最大的神经疾病之一，治疗方案有限。因此，迫切需要新的治疗方法。在组织梗塞的早期阶段，脑缺血会导致严重的且往往是不可逆的线粒体损伤。反过来，受损的线粒体会产生自由基，促进细胞死亡，从而进一步加剧脑损伤。对缺血脑中线粒体功能如何受损的机械性理解可能会揭示保护线粒体的新方法，并导致开发新的神经保护策略。我们发现线粒体蛋白抑制素(PHB)被缺血预适应上调，并证明通过基因转移表达PHB可以保护培养的皮质神经元免受缺氧性葡萄糖剥夺的影响，并保护海马CA1区神经元免受短暂性前脑缺血所致的迟发性变性。这些研究清楚地表明PHB具有很强的神经保护潜力，但与神经保护有关的机制，特别是那些与线粒体有关的机制，需要阐明。为此，我们开发了条件性PHB转基因(PHB-TG)小鼠，在神经元或星形胶质细胞中选择性表达PHB。利用这些小鼠，我们建议测试这一假设，即PHB通过调节关键的线粒体功能，调节线粒体对缺血的敏感性，并保护缺血的大脑免受损伤。特别是，我们将使用大脑中动脉(MCA)短暂闭塞造成的局灶性脑缺血模型来研究PHB的条件神经元或星形胶质细胞表达是否改善缺血性脑损伤。此外，我们将研究PHB保护线粒体的生物能量学机制，以及它通过调节缺血神经元中线粒体的融合、分裂和嵴结构在维持线粒体网络完整性中的作用。因此，本研究的结果将促进我们对PHB如何调节线粒体结构、功能和动力学的理解，并将在调节PHB表达的基础上为缺血性损伤提供新的治疗靶点。这些发现还将促进我们对通过调节线粒体动力学来调控神经元生存和死亡的基本过程的理解，并有可能确定与线粒体功能障碍有关的其他神经疾病的线粒体靶向治疗策略。