Bioenergetics and Neuronal Network Remodeling in a Rodent Model of Temporal Lobe Epilepsy

颞叶癫痫啮齿动物模型中的生物能量学和神经元网络重塑

• 批准号: 10550184
• 负责人: Yijen Lin Wu
• 金额: $ 19.49万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10550184
• 关键词: 2,4-Dinitrophenol; Acute; Adult; Affect; Anesthesia procedures; Animals; Anticonvulsants; Attenuated; Bioenergetics; Biological Assay; Biological Markers; Brain; Brain Injuries; Child; Childhood; Chronic; Clinical; Complex; Data; Defect; Development; Diffusion Magnetic Resonance Imaging; Dinitrophenols; Disease; Early Intervention; Energy-Generating Resources; Epilepsy; Epileptogenesis; Evolution; Functional Magnetic Resonance Imaging; Functional disorder; Future; Genes; Genetic; Goals; Hypoxia; Impairment; Inherited; Injury; Kainic Acid; Knowledge; Legal patent; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Membrane Potentials; Metabolic; Methods; Mitochondria; Modeling; Molecular; Monitor; Motor Seizures; Mus; N-acetylaspartate; Neuronal Injury; Neurons; Oxidative Phosphorylation; Patients; Pharmaceutical Preparations; Play; Positioning Attribute; Process; Protocols documentation; Proxy; Pyruvate; Rattus; Refractory; Respiration; Respiratory Chain; Rodent; Rodent Model; Rotenone; Route; Seizures; Severities; Signal Transduction; Site; Spirometry; Status Epilepticus; Temporal Lobe Epilepsy; Testing; Time; Tissues; Translating; Validation; acquired epilepsy; epileptic encephalopathies; experience; genomic locus; in vivo; mitochondrial dysfunction; neural network; novel; oxidation; pharmacologic; predictive marker; resilience; risk stratification; spatiotemporal; tool; valproate

Epilepsy affects 3 million adults and 450,000 children in the US. One-third of chronic epilepsy is intractable to current antiseizure medications. Temporal lobe epilepsy (TLE), the most frequent form of acquired epilepsy, is typically initiated by brain injury, such as status epilepticus (SE), followed by a latent period wherein molecular and cellular remodeling occurs leading to chronic epilepsy. The process of remodeling is poorly understood. Not every patient who experiences episodic SE will progress to TLE, and the latent period of epileptogenesis can vary from weeks to years. There is a critical need for new mechanistic understanding and early recognition of post-SE TLE for risk stratification and better management. Mitochondrial dysfunction is increasingly recognized as an inciting factor for TLE, not only acutely after SE, but also contributing to epileptogenesis for refractory TLE. However, there are major knowledge gaps in disease thresholds and a lack of sensitive in vivo tools to detect and monitor the subclinical epileptogenesis process for early intervention before epilepsy is established. Our long-term goal is to understand the remodeling process that leads from SE to TLE. As an important step towards this, we are now in a strong position to test the HYPOTHESIS that a novel 4D oxy-wavelet MRI can be a proxy to detect foci with mitochondrial dysfunctions in post-SE injury that can contribute to TLE development. The focus of the current proposal is to validate and establish 4D oxy-wavelet MRI as a biomarker for identifying brain foci with mitochondrial dysfunctions. We will first validate 4D oxy-wavelet MRI as a non-invasive, region-specific means of monitoring mitochondrial function in the brain. We will use the well-known mitochondrial drugs, rotenone and 2,4-dinitrophenol, to pharmacologically impair or enhance mitochondrial respiration, respectively. Then we will monitor spatiotemporal evolution of region-specific changes in mitochondrial functions with 4D oxy-wavelet MRI in a post-SE TLE rat model. The 4D oxy-wavelet MRI signal will be correlated with ex vivo mitochondrial functional assays, including Oroboros respirometry, and brain metabolic profiling with in vivo MR spectroscopy. Our study will validate 4D oxy-wavelet MRI as a non-invasive method for monitoring mitochondrial activity in the brain. Using a rat model of post-SE TLE, we will use the new MRI tool to observe temporal and region- specific changes of mitochondrial function. These data can advance use of the 4D oxy-wavelet MRI as a non- invasive biomarker for predicting post-SE TLE. As this method is non-invasive, it can be translated to clinical setting in the future.

在美国，癫痫影响着300万成年人和45万儿童。三分之一的慢性癫痫是 对目前的抗癫痫药物无效。颞叶癫痫（TLE），最常见的获得性癫痫 癫痫通常由脑损伤引发，例如癫痫持续状态（SE），随后是潜伏期，其中 发生分子和细胞重塑，导致慢性癫痫。重塑的过程很糟糕 明白并非每一个经历发作性SE的患者都会发展为TLE，并且TLE的潜伏期可能与TLE有关。 癫痫发生可以从数周到数年不等。迫切需要新的机械理解， 早期识别SE后TLE，以进行风险分层和更好的管理。 线粒体功能障碍越来越多地被认为是TLE的一个诱发因素，不仅是急性TLE后， SE，但也有助于难治性TLE的癫痫发生。然而，在以下方面存在重大知识差距： 疾病阈值和缺乏敏感的体内工具来检测和监测亚临床癫痫发生 在癫痫发作之前进行早期干预。我们的长期目标是了解 从SE到TLE的过程。作为实现这一目标的重要一步，我们现在处于有利地位，可以测试 假设一种新的4D oxy-wavelet MRI可以作为检测线粒体功能障碍病灶的替代， SE后损伤可能导致TLE发展。本提案的重点是验证和 建立4D oxy-wavelet MRI作为识别线粒体功能障碍脑病灶的生物标志物。我们将 首次验证4D oxy-wavelet MRI作为监测线粒体功能的非侵入性、区域特异性方法 在大脑中。我们将使用众所周知的线粒体药物鱼藤酮和2，4-二硝基苯酚， 分别损害或增强线粒体呼吸。然后我们将监控时空 SE TLE后大鼠线粒体功能的4D oxy-wavelet MRI区域特异性变化 模型4D氧小波MRI信号将与离体线粒体功能测定相关，包括 Oroboros呼吸测定法和脑代谢分析与体内MR波谱。 我们的研究将验证4D oxy-wavelet MRI作为监测线粒体活性的非侵入性方法 在大脑中。使用SE TLE后大鼠模型，我们将使用新的MRI工具观察颞叶和区域- 线粒体功能的特定变化。这些数据可以推进4D氧小波MRI作为非成像系统的使用。 预测SE后TLE侵袭性生物标志物。由于这种方法是无创的，它可以转化为临床 设定在未来。