ROLE OF PROHIBITIN IN ISCHEMIC BRAIN INJURY

抑制素在缺血性脑损伤中的作用

• 批准号: 8303293
• 负责人: Ping Zhou
• 金额: $ 36.23万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303293
• 关键词: ATP Synthesis Pathway; Alteplase; Apoptosis; Bioenergetics; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Cerebral Ischemia; Cerebrum; Cessation of life; Clinical; Complex; Cytoprotective Agent; Defense Mechanisms; Down-Regulation; Electrons; Functional disorder; Gene Transfer; Glucose; Health; Hippocampus (Brain); In Vitro; Injury; Ischemia; Ischemic Brain Injury; Ischemic Preconditioning; Ischemic Stroke; Membrane Proteins; Methods; Mitochondria; Mitochondrial Membrane Protein; Modeling; Mus; N-Methylaspartate; Neuronal Injury; Neurons; Organ; Organelles; Oxidative Stress; Oxygen; Patients; Pattern; Phase; Predisposition; Process; Production; Prosencephalon; Proteins; Proteomics; Reactive Oxygen Species; Recombinant adeno-associated virus (rAAV); Recovery; Resistance; Respiratory Chain; Role; Small Interfering RNA; Stimulus; Stroke; Testing; Therapeutic; Time; Up-Regulation; Viral Genes; cell type; deprivation; effective therapy; improved; improved functioning; in vivo; in vivo Model; inhibitor/antagonist; neuronal survival; neuroprotection; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; overexpression; preconditioning; prohibitin; protective effect; public health relevance; research study; spatiotemporal; treatment strategy

DESCRIPTION (provided by applicant): Prohibitin (PHB) is a mitochondrial inner membrane protein that may preserve cellular integrity by stabilizing the function of complex I, the electrons entry point into the respiratory chain, and reducing production of mitochondrial reactive oxygen species. In a proteomic study seeking to identify potential neuroprotective proteins expressed in murine models of ischemic tolerance, we found that PHB expression is increased in neuronal mitochondria. These observations raise the possibility that PHB upregulation in preconditioning models promotes neuronal survival, while its downregulation in ischemia facilitates neuronal death. Thus, the long-term objectives of this application are to elucidate the roles of PHB in the brain damage produced by cerebral ischemia and to assess its neuroprotective potential. In particular, we will test the central hypothesis that PHB, by influencing the mitochondrial resistance to injury, is a key determinant of neuronal fate in the ischemic brain. The proposed experiments will use in vitro (oxygen-glucose deprivation), and in vivo (transient forebrain ischemia) models of cerebral ischemic injury. Viral gene transfer and small interfering RNA (siRNA) will be used to increase or decrease PHB expression in neuronal cultures or in the mouse hippocampus. Mitochondrial function will be assessed in neuronal cultures or in isolated mitochondria to explore the mechanisms of the effect of PHB. The following hypotheses will be tested: (a) Hypoxia-ischemia downregulates PHB, a reduction that decreases endogenous defense mechanisms and may increase the susceptibility of the brain to injury; (b) Expression of PHB in neuronal cultures is neuroprotective, while its downregulation increases vulnerability to injury; (c) Expression of PHB in the mouse hippocampus protects vulnerable neurons from the damage produced by transient forebrain ischemia; (d) The mechanisms of the neuroprotective effect of PHB involve complex I stabilization and reduced production of mitochondrial reactive oxygen species. PUBLIC HEALTH RELEVANCE: The proposed studies will investigate a novel aspect of the pathobiology of PHB, related to its role in the death and survival of ischemic neurons. The findings will advance our understanding of the fundamental processes regulating ischemic neuronal death, and have the potential of identifying new treatment strategies for ischemic stroke.

描述（由申请人提供）：Prohibitin（PHB）是一种线粒体内膜蛋白，可通过稳定复合物I（电子进入呼吸链的入口点）的功能并减少线粒体活性氧的产生来保持细胞完整性。在一项蛋白质组学研究中，我们发现在缺血耐受的小鼠模型中，PHB的表达在神经元线粒体中增加。这些观察结果提高了在预处理模型中PHB上调促进神经元存活的可能性，而在缺血中其下调促进神经元死亡。因此，本申请的长期目标是阐明PHB在脑缺血引起的脑损伤中的作用，并评估其神经保护潜力。特别是，我们将测试中心的假设，即通过影响线粒体对损伤的抵抗力，是缺血性脑神经元命运的关键决定因素。拟议的实验将使用脑缺血性损伤的体外（氧-葡萄糖剥夺）和体内（短暂性前脑缺血）模型。将使用病毒基因转移和小干扰RNA（siRNA）来增加或减少神经元培养物或小鼠海马中的PHB表达。将在神经元培养物或分离的线粒体中评估线粒体功能，以探索PHB的作用机制。将检验以下假设：（a）缺氧-缺血下调PH B，这种下调降低内源性防御机制并可能增加脑对损伤的敏感性;（B）神经元培养物中PH B的表达具有神经保护作用，而其下调增加对损伤的脆弱性;（c）小鼠海马中PH B的表达保护脆弱神经元免受短暂前脑缺血产生的损伤;（d）聚羟基丁酸的神经保护作用的机制涉及复合物I稳定化和减少线粒体活性氧的产生。 公共卫生关系：拟议的研究将调查一个新的方面的病理生物学的聚羟基丁酸酯，有关其作用的死亡和存活的缺血性神经元。这些发现将促进我们对缺血性神经元死亡的基本调控过程的理解，并有可能为缺血性卒中确定新的治疗策略。