Modulation of neural function in energy failure

能量衰竭时神经功能的调节

• 批准号: 8693035
• 负责人: Juan M. Pascual
• 金额: $ 34.43万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8693035
• 关键词: Absence Epilepsy; Address; Anesthesia procedures; Animal Model; Anticonvulsants; Biochemical; Brain; Brain region; Carbon; Carbon Dioxide; Cell Culture System; Cells; Cerebral cortex; Cerebrum; Citric Acid Cycle; Clinical; Conscious; Data; Defect; Development; Diet; Dietary Fats; Disease; Disorder of neurometabolic regulation; Electrocorticogram; Electrophysiology (science); Encephalopathies; Energy Metabolism; Epilepsy; Epileptogenesis; Equilibrium; Failure; Fatty Acids; Fatty acid glycerol esters; Food; Functional disorder; GABA Receptor; Generations; Genes; Glucose; Glucose Transporter; Glutamate Receptor; Glutamates; Goals; Health; Hepatic; Human; Impairment; In Vitro; Inborn Genetic Diseases; Inherited; Intervention; Intractable Epilepsy; Investigation; Ketone Bodies; Ketones; Knowledge; Laboratories; Life; Mass Spectrum Analysis; Measures; Medical; Mental Retardation; Metabolic; Metabolic Brain Diseases; Metabolic Diseases; Metabolism; Methodology; Methods; Mission; Modeling; Modification; Motivation; Motor; Mus; Mutation; Neurologic; Neurologic Dysfunctions; Neurons; Neurophysiology - biologic function; Neurotransmitters; Nutrient; Patients; Performance; Process; Reaction; Research; Resistance; SLC2A1 gene; Seizures; Site-Directed Mutagenesis; Slice; Synapses; Testing; Thalamic structure; Therapeutic; Translating; Treatment Efficacy; United States National Institutes of Health; Water; Work; base; behavioral impairment; brain metabolism; brain tissue; disabling disease; gamma-Aminobutyric Acid; glucose metabolism; glucose transport; glucose uptake; human data; human disease; innovation; ketogenic diet; ketogentic; mouse model; neocortical; neurotransmission; novel; novel therapeutics; palliative; relating to nervous system; stem; synaptic function; therapeutic target

DESCRIPTION (provided by applicant): Human glucose transporter type I-deficiency (G1D) leads to reduced brain glucose influx and neurological dysfunction principally manifested as epilepsy. Normally, most glucose is fully degraded into CO2 and water for brain energy generation via the tricarboxylic acid (TCA) cycle, which is also central to the synthesis and utilization of the neurotransmitters glutamate and GABA. Importantly, a fraction of glucose does not directly generate energy, but refills natural TCA cycle precursor loss through a reaction termed anaplerosis. Despite these long-established biochemical principles, it is unclear how most diseases that impair brain metabolism and cause seizures disrupt excitability within brain tissue (rather than in vitro), including G1D, which leads to spike-wave epilepsy. This knowledge gap about mechanisms critically limits treatment, as illustrated by anticonvulsant resistance in G1D, which is also the rule in many other neurometabolic disorders. Our laboratory and clinical long-term goal is to mechanistically understand these brain metabolism-excitability relationships in patients and mouse models to develop pharmacological and dietary therapies. The objectives of this application are to characterize hyperexcitability in a novel, robust G1D mouse model and to mitigate it by stimulating both anaplerosis and the TCA cycle with dietary substrates. Our human data and preliminary laboratory results, such as the finding of TCA cycle precursor depletion and of abnormal neocortical and thalamic excitability in G1D mice, justify investigating these mechanisms in more depth to understand epileptic hypersynchronization as a central feature of human and murine G1D. This leads to the main hypothesis that synaptic dysfunction is critical for disease pathophysiology. The proposal also includes the therapeutic consideration that even-carbon ketones, generated from common dietary fats or a ketogenic diet, can fuel the TCA cycle and ameliorate seizures in G1D, but are not anaplerotic. In contrast, our data open a new therapeutic opportunity because administered odd-carbon fat refills brain TCA cycle precursors efficiently in G1D; leading to the additional hypothesis that it restores neural functio more effectively than even-carbon fat via anaplerosis. The hypotheses will be tested in three aims: 1) Investigate the basis of cortical hyperexcitability in G1D; 2) Expand this mechanistic approach to the thalamus; 3) Restore brain metabolism and function via anaplerosis. The proposal is significant because its focus on metabolism-excitability relationships and anaplerosis in brain tissue using a very informative mouse model represents a shift in approach to neurometabolic diseases, where electrophysiology, 13C NMR and mass spectrometry offer a complementary understanding of mechanisms conducive to potential therapies. Particularly innovative is to combine an investigation of synaptic function in circuits or brain regions crucial for epilepsy, impaired behavior or mental retardation with the development of methodology sensitive to conscious mouse brain metabolism with broad applicability to other encephalopathies. In summary, we expect that this proposal will help define G1D as a synaptic disorder and render it amenable to excitable or metabolic target modification.

描述（由申请人提供）：人类葡萄糖转运蛋白 I 型缺陷（G1D）导致大脑葡萄糖流入减少和主要表现为癫痫的神经功能障碍。正常情况下，大多数葡萄糖通过三羧酸（TCA）循环完全降解为二氧化碳和水，为大脑产生能量，这也是神经递质谷氨酸和 GABA 合成和利用的核心。重要的是，一小部分葡萄糖并不直接产生能量，而是通过称为回补的反应来补充自然的 TCA 循环前体损失。尽管有这些长期确立的生化原理，但目前尚不清楚大多数损害脑代谢并导致癫痫发作的疾病如何破坏脑组织内（而不是体外）的兴奋性，包括导致棘波癫痫的 G1D。这种关于机制的知识差距严重限制了治疗，G1D 的抗惊厥耐药性就表明了这一点，这也是许多其他神经代谢疾病的规律。我们实验室和临床的长期目标是从机制上理解患者和小鼠模型中的这些大脑代谢与兴奋性关系，以开发药理学和饮食疗法。本应用的目的是表征新型、稳健的 G1D 小鼠模型中的过度兴奋性，并通过用膳食底物刺激回补和 TCA 循环来减轻过度兴奋性。我们的人类数据和初步实验室结果，例如在 G1D 小鼠中发现 TCA 循环前体耗尽以及异常新皮质和丘脑兴奋性，证明了更深入研究这些机制的合理性，以了解癫痫超同步作为人类和小鼠 G1D 的核心特征。这导致了一个主要假设：突触功能障碍对于疾病病理生理学至关重要。该提案还包括治疗方面的考虑，即由普通膳食脂肪或生酮饮食产生的偶碳酮可以促进 TCA 循环并改善 G1D 的癫痫发作，但不会补全。相比之下，我们的数据开启了一个新的治疗机会，因为在 G1D 中施用奇数碳脂肪可以有效地补充大脑 TCA 循环前体；导致额外的假设，即它通过回补比均匀碳脂肪更有效地恢复神经功能。这些假设将在三个目标上进行检验：1）研究 G1D 皮质过度兴奋的基础； 2）将这种机械方法扩展到丘脑； 3）通过回补恢复大脑的新陈代谢和功能。该提案意义重大，因为它使用信息丰富的小鼠模型关注脑组织中的代谢-兴奋性关系和回补，代表了神经代谢疾病方法的转变，其中电生理学、13C NMR和质谱提供了对有利于潜在疗法的机制的补充理解。特别创新的是结合对神经回路或大脑区域中突触功能的研究 随着对有意识小鼠大脑代谢敏感的方法的开发，该方法可广泛应用于其他脑病。总之，我们预计该提案将有助于将 G1D 定义为一种突触疾病，并使其易于兴奋或代谢目标修饰。