Role of Prohibitin Nitrosylation in its Neuroprotective Functions

抑制素亚硝基化在其神经保护功能中的作用

• 批准号: 10626154
• 负责人: Ping Zhou
• 金额: $ 42.37万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626154
• 关键词: Address; Affect; Astrocytes; Binding; Bioenergetics; Biological Assay; Brain; Brain Injuries; Brain Pathology; Cells; Cerebral Ischemia; Cerebrum; Coculture Techniques; Code; Crista ampullaris; Cysteine; Electron Microscopy; Embryo; Environment; Event; Gel; Genus Hippocampus; Glucose; In Vitro; Ischemia; Ischemic Brain Injury; Ischemic Neuronal Injury; Knock-in; Knock-in Mouse; Laboratories; Life; Link; Maintenance; Mediating; Messenger RNA; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Mus; Mutant Strains Mice; Mutate; Mutation; Neuroglia; Neurologic; Neurons; Nitric Oxide; Nitric Oxide Donors; Oxidative Phosphorylation; Oxygen; Pathology; Patients; Pattern; Phosphorylation; Play; Positioning Attribute; Post-Translational Protein Processing; Process; Production; Protein S; Proteins; Reactive Oxygen Species; Regulation; Respiratory Chain; Role; S-Nitrosoglutathione; Scaffolding Protein; Somatic Mutation; Specificity; Stress; Stroke; Structure; System; Testing; Therapeutic; Transgenic Mice; Work; artery occlusion; brain tissue; cell type; deprivation; design; in vivo; inhibitor; ischemic injury; mitochondrial dysfunction; mutant; nervous system disorder; neuron loss; neuronal survival; neuroprotection; novel; prevent; prohibitin; protein protein interaction; restoration; stroke risk; targeted treatment; therapy design; translational potential; treatment strategy

Project Summary/Abstract The mitochondrial protein Prohibitin (PHB) is essential for life. Its importance to cellular activities is attested by the fact that deletion of PHB is embryonic lethal in mice and that to date no mutation has been found in the coding region of PHB in any neurological disease conditions, indicating that PHB integrity is essential and that somatic mutation is detrimental. Our recent work has demonstrated that PHB has remarkable neuroprotective potential against ischemic brain injury with an underlying mitochondrial associated mechanism. Its expression is critical for mitochondrial function in stress situations. However, how this important protein that are stable at both mRNA and protein levels, is functionally regulated in neuroprotection, as well as how it is dysregulated in other neurological conditions, remain surprisingly unknown. In exploring the mechanisms of PHB regulation, we discovered that nitric oxide (NO) is required for PHB expression mediated neuroprotection. Therefore, we investigated the interaction between NO and PHB and found that NO modifies PHB post-translationally, through protein s-nitrosylation, a novel regulatory mechanism similar to protein phosphorylation. In this application, we propose to study the effects of PHB S-nitrosylation and the mechanisms underlying functional regulation of PHB by NO. Our central hypothesis is that nitrosylation is critical for PHB’s neuroprotective function and, consequently, disturbances of PHB nitrosylation are detrimental and contribute to pathology. We will use a novel mutant knock-in mouse, in which the sole cysteine residue of PHB protein is mutated so that PHB cannot be nitrosylated, to analyze the mechanisms of NO regulation and the effects of loss of PHB nitrosylation on PHB function, in the settings of brain ischemic injury in association with mitochondria structural alterations. Three specific aims will systematically test the hypothesis. The results of the proposed studies will reveal a previously unrecognized regulatory mechanism of PHB which we believe is crucial to facilitate the design of potential therapies that could ultimately benefit patients at risk of stroke and other neurological diseases.

项目摘要/摘要 线粒体蛋白禁止素（PHB）对生命至关重要。它对细胞活动的重要性 PHB的删除是小鼠的胚胎致死的事实证明，迄今为止尚未 在任何神经系统疾病条件下，在PHB的编码区域都发现了突变， 表明PHB完整性是必不可少的，并且体细胞突变是有害的。我们的最新消息 工作表明，PHB具有针对缺血性的显着神经保护潜力 脑损伤具有潜在的线粒体相关机制。它的表达对于 在应力情况下的线粒体功能。但是，这种重要的蛋白质如何稳定 mRNA和蛋白质水平均在神经保护中受到功能调节，以及它的方式 在其他神经系统条件下失调的失调仍然令人惊讶地未知。在探索 PHB调节机制，我们发现PHB需要一氧化氮（NO） 表达介导的神经保护。因此，我们调查了NO之间的相互作用 和PHB，并发现在翻译后通过蛋白S-亚硝基化（a）不改变PHB 新型调节机制类似于蛋白质磷酸化。在此应用程序中，我们提出了 研究PHB S-亚硝基化的作用和功能调节的机制 PHB的否。我们的中心假设是，亚硝基化对PHB至关重要 神经保护功能，因此，PHB亚硝基化的灾难是 有害并有助于病理学。我们将在 PHB蛋白的唯一半胱氨酸居住是突变的，因此PHB不能被硝基化， 分析无调节的机制以及pHB硝基化对PHB的影响 功能，在与线粒体结构相关的脑缺血性损伤的环境下 改变。三个具体目标将系统地检验该假设。结果 拟议的研究将揭示PHB先前未知的调节机制 认为对可能最终受益的潜在疗法的设计至关重要 患有中风和其他神经系统疾病的患者。