GABAergic Inhibition and the Ketogenic Diet

GABA能抑制和生酮饮食

• 批准号: 6556580
• 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 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6556580
• 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）：本申请适用于独立科学家奖（K02）。该候选人是一名儿科神经科医生，对儿童癫痫有特殊兴趣，目前正处于 K08 (MCSDA) 资助的最后一年。他最近搬到了加州大学欧文分校 (UCI)。 UCI拥有国际认可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，尤其是在他刚刚建立独立实验室的关键时刻。在 K08 资助的早期，该候选人对癫痫发育动物模型、Kv1.1 钾通道敲除小鼠（即 Kcna1 缺失突变体）进行了详细研究。后来，申请人对生酮饮食（KD）抗惊厥功效的机制进行了研究，生酮饮食是一种已确立但仍知之甚少的顽固性癫痫治疗方法。 KD 是一种高脂肪、低碳水化合物和低蛋白质饮食，旨在模仿禁食时出现的早期生化变化。 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 GABAergic 系统在 KD 癫痫发作控制中的潜在作用，并在此过程中建立和验证临床相关的 KD 动物模型。作为次要目标，将确定慢性酮体暴露是否可以增强大脑中的 GABA 抑制。此外，还将解决生酮饮食是否能够在治疗期间发挥持久抗癫痫作用的问题，从而为未来旨在确定生酮饮食抗癫痫作用机制基础的研究奠定基础。为了实现这些目标，我们将研究 KD 对 Kcna1 缺失突变体的影响。此外，还将研究酮​​体对这些小鼠海马器官切片培养物的长期影响。拟议的研究将采用神经解剖学（即组织学、免疫细胞化学、原位杂交）和功能性（即视频脑电图监测、细胞电生理学）技术。预计这些研究的结果将揭示 KD 在癫痫发生中的潜在作用，特别是因为它与 GABA 能抑制的作用有关