GABAergic Inhibition and the Ketogenic Diet

GABA能抑制和生酮饮食

• 批准号: 6697494
• 负责人: Jong Min Rho
• 金额: $ 14.54万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6697494
• 关键词: anticonvulsants; brain disorder chemotherapy; dietary carbohydrates; dietary proteins; disease /disorder model; electroencephalography; electrophysiology; epilepsy; gamma aminobutyrate; gene targeting; genetically modified animals; hippocampus; histopathology; immunocytochemistry; in situ hybridization; inhibitor /antagonist; ketone body; laboratory mouse; liver metabolism; model design /development; mutant; neuroanatomy; neuropharmacology; nonhuman therapy evaluation; potassium channel; tissue /cell culture

DESCRIPTION (provided by applicant): This application is for an Independent Scientist Award (K02). The candidate is a pediatric neurologist with a specialty interest in childhood epilepsy, and is currently in the final year of K08 (MCSDA) funding. He recently relocated to the University of California at Irvine (UCI). UCI hosts an internationally recognized basic neuroscience research community, and is well suited to the career development needs of the candidate, especially at this critical time when he has just established an independent laboratory. During the early period of K08 funding, the candidate performed detailed studies of a developmental animal model of epilepsy, the Kv1.1 potassium channel knockout mouse (i.e., the Kcna1-null mutant). Later, the applicant pursued research into the mechanisms underlying the anticonvulsant efficacy of the ketogenic diet (KD), an established but still poorly understood treatment for intractable epilepsy. The KD is a high-fat, low carbohydrate and low-protein diet designed to mimic the early biochemical changes seen upon fasting. The hallmark feature of the KD is the production of the ketone bodies by the liver. The fundamental goal of the proposed studies is to assess the potential role of the GABAergic system in contributing to seizure control by the KD, and in the process establish and validate a clinically relevant animal model of the KD. As a secondary goal, it will be determined whether chronic ketone body exposure can enhance GABAergic inhibition in the brain. Further, the question of whether the KD can exert a lasting antiepileptic effect, beyond the duration of therapy, will be addressed, thereby setting the stage for future studies aimed at determining a mechanistic basis for an anti-epileptogenic effect of the KD. Toward these goals, the effects of the KD on the Kcna1-null mutant will be investigated. In addition, the long-term impact of ketone bodies in hippocampal organotypic slice cultures prepared from these mice will be studied. Neuroanatomical (i.e., histological, immunocytochemical, in situ hybridization) and functional (i.e., video-EEG monitoring, cellular electrophysiological) techniques will be employed in the proposed studies. It is expected that the results of these investigations will shed light on the potential role of the KD in epileptogenesis, especially as it relates to effects on GABAergic inhibition

描述（由申请人提供）：此应用程序是一个独立的科学家奖（K 02）。该候选人是一名儿科神经学家，对儿童癫痫有特殊兴趣，目前正处于K 08（MCSDA）资助的最后一年。他最近搬到了位于欧文的加州大学（UCI）。UCI拥有国际公认的基础神经科学研究社区，非常适合候选人的职业发展需求，特别是在他刚刚建立独立实验室的关键时期。在K 08资助的早期，候选人对癫痫的发育动物模型Kv1.1钾通道敲除小鼠（即，Kcna 1-无效突变体）。后来，申请人继续研究生酮饮食（KD）抗惊厥疗效的机制，这是一种已确立但仍知之甚少的难治性癫痫治疗方法。KD是一种高脂肪、低碳水化合物和低蛋白饮食，旨在模拟禁食后观察到的早期生化变化。KD的标志性特征是肝脏产生酮体。拟议研究的基本目标是评估GABA能系统在KD控制癫痫发作中的潜在作用，并在此过程中建立和验证KD的临床相关动物模型。作为次要目标，将确定慢性酮体暴露是否可增强大脑中的GABA能抑制。此外，KD是否可以发挥持久的抗癫痫作用，超过治疗的持续时间的问题，将得到解决，从而为未来的研究，旨在确定一个机制的基础上的KD的抗癫痫作用。为了实现这些目标，将研究KD对Kcna 1无效突变体的影响。此外，还将研究酮体对从这些小鼠制备的海马器官型切片培养物的长期影响。神经解剖学（即，组织学、免疫细胞化学、原位杂交）和功能（即，视频脑电图监测，细胞电生理学）技术将被用于拟议的研究。预期这些研究的结果将阐明KD在癫痫发生中的潜在作用，特别是当它与GABA能抑制作用有关时