Mitochondrial Sirtuin-3 dysregulation in epileptogenesis

癫痫发生中的线粒体 Sirtuin-3 失调

• 批准号: 9385643
• 负责人: MANISHA N PATEL
• 金额: $ 4.82万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9385643
• 关键词: Acetylation; Aging; Animal Model; Antioxidants; Attenuated; Bioenergetics; Brain; Cell physiology; Chronic; Comorbidity; Complex; Data; Deacetylase; Electroencephalography; Enzymes; Epilepsy; Epileptogenesis; Etiology; Event; Experimental Models; Functional disorder; Goals; Homeostasis; Impaired cognition; Impairment; Incidence; Injury; Knockout Mice; Knowledge; Lighting; Link; Mass Spectrum Analysis; Mediator of activation protein; Memory impairment; Metabolic; Metabolic Control; Mitochondria; Mitochondrial Proteins; Modeling; Monitor; Mus; NADH; Nature; Neurons; Nicotinamide adenine dinucleotide; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Pharmacology; Post-Translational Protein Processing; Production; Prosencephalon; Protein Acetylation; Reactive Oxygen Species; Research; Role; SOD2 gene; Seizures; Sirtuins; Site; Source; Supplementation; Temporal Lobe Epilepsy; Testing; Therapeutic; age related; base; cognitive function; cognitive testing; human imaging; imaging study; improved; infancy; innovation; insight; interest; mitochondrial dysfunction; nervous system disorder; neuron loss; neuronal excitability; novel; novel therapeutic intervention; programs; public health relevance; restoration

 DESCRIPTION (provided by applicant): Mitochondria control critical cell functions that can impact epilepsy and its comorbidities. Key features of temporal lobe epilepsy (TLE) such as its progressive nature, rising incidence with aging and bioenergetic demands suggest mitochondrial involvement. Mitochondrial dysfunction has been implicated in various neurological diseases including experimental models of TLE. However, the precise mechanisms underlying mitochondrial dysfunction in TLE remain unclear. The proposal builds upon our previous discoveries of impaired mitochondrial redox status and bioenergetics in experimental models of TLE. A central mediator that links mitochondrial oxidative stress with bionenergetic dysfunction is sirtuin-3 (SIRT3), a mitochondrial nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase known to maintain metabolic homeostasis. SIRT3 is exquisitely sensitive to aging and serves as a major switch to regulate mitochondrial protein acetylation to control metabolic flux and energy. It is hypothesized that decreased SIRT3 activity and consequent increases in mitochondrial protein acetylation contribute to the impaired bioenergetics in TLE. Using novel mass spectrometry-based quantitative mitochondrial acetylomics, brain-specific SIRT3 conditional knockout mice and restorative therapies, we plan to explore the role of SIRT3 in TLE. Aim 1 will determine if SIRT3 dysfunction occurs following chemoconvulsant-induced epilepsy. Aim 2 will determine if conditional deletion of SIRT3 or its target, Sod2 is sufficient to cause age-related epilepsy and cognitive dysfunction and Aim 3 will determine if restoration of SIRT3 activity by supplementation with NAD+ precursor attenuates deficits observed in chemoconvulsant-induced TLE. Collectively, this project can identify a novel role of SIRT3 as a mediator of mitochondrial dysfunction in chronic seizures and/or cognitive impairment associated with TLE and provide a therapeutic approach for its treatment.

 描述(申请人提供)：线粒体控制关键细胞功能，可影响癫痫及其合并症。颞叶癫痫(TLE)的主要特征，如进行性，发病率随年龄增长和生物能量需求提示线粒体参与。线粒体功能障碍与多种神经系统疾病有关，包括实验性的TLE模型。然而，TLE线粒体功能障碍的确切机制仍不清楚。该建议建立在我们之前在TLE实验模型中发现的线粒体氧化还原状态受损和生物能量学的基础上。将线粒体氧化应激与生物能功能障碍联系起来的一个中心介质是sirtuin-3(SIRT3)，它是一种依赖于线粒体烟酰胺腺嘌呤二核苷酸(NAD+)的脱乙酰酶，可维持代谢平衡。SIRT3对衰老非常敏感，是调节线粒体蛋白质乙酰化以控制代谢流量和能量的主要开关。推测SIRT3活性降低和线粒体蛋白乙酰化增加是TLE生物能量学受损的原因。利用新的基于质谱学的定量线粒体乙酰组学、脑特异性SIRT3条件性基因敲除小鼠和恢复疗法，我们计划探索SIRT3在TLE中的作用。目的1将确定SIRT3功能障碍是否发生在化学惊厥诱导的癫痫后。目标2将确定SIRT3或其靶基因的条件缺失是否足以导致年龄相关性癫痫和认知功能障碍，目标3将确定通过补充NAD+前体来恢复SIRT3的活性是否能减轻化疗惊厥诱导的TLE中观察到的缺陷。总之，该项目可以确定SIRT3在慢性癫痫发作和/或与TLE相关的认知损害中作为线粒体功能障碍的中介的新角色，并为其治疗提供一种治疗方法。