The Impact of Vitamin D on mTOR Signaling, Seizures, and Motor Behavior in a Mouse Model of Hyperactive mTOR Induced Epilepsy and Ataxia

项目总结/摘要 哺乳动物雷帕霉素靶蛋白（mTOR）信号传导增加是治疗抵抗性癫痫的已知原因。 mTOR的负调节因子的病理性突变导致mTOR信号传导过度活跃，并且已经被证实是一种新的免疫抑制剂。 在癫痫患者的前脑和小脑中发现。最近的研究表明，小脑 导致癫痫的发生。然而，对过度活跃的mTOR诱导的癫痫的研究 几乎完全集中在下丘脑和前脑结构上。个人发展 与小脑中mTOR过度活跃相关的癫痫发作通常对药物治疗有抗性， 需要介入治疗并进行侵入性脑外科手术。在严重的情况下，手术可能无法控制生长，必须 重复因此，迫切需要新的治疗方法。初步数据显示，补充维生素D可能 在过度活跃mTOR诱导癫痫和共济失调的小鼠模型中抑制癫痫。这项建议旨在 确定在青春期开始补充维生素D是否会减少癫痫发作和并发症， 发生运动损伤（Aim 1A），在多动的啮齿动物模型中恢复成年期的mTOR信号传导。 mTOR诱导癫痫和共济失调（Aim 1B）并逆转小脑颗粒细胞肥大（Aim 1C）。的 F99期研究将提供分子机制研究方面的专业知识和培训。 神经系统疾病的潜在遗传原因和药物治疗的新机制的测试 治疗F99阶段的完成将提供培训，作为K 00的跳板 相位贝勒大学拥有强大的分子生物科学和成像核心，一个专门的毕业生， 写作中心，教师和研讨会致力于专业培训和教学。所附提案 F99和K 00阶段的培训计划概述了从博士前实习生成功过渡到 一位独立的研究者，研究神经发育障碍的治疗方法。

Project Summary / Abstract Increased mammalian target of rapamycin (mTOR) signaling is a known cause of treatment resistant epilepsy. Pathological mutations to negative regulators of mTOR lead to hyperactive mTOR signaling and have been found in the forebrain and cerebellum of individuals with epilepsy. The cerebellum has recently been shown to contribute to the development of epilepsy. However, research in hyperactive mTOR induced epilepsy has almost exclusively been focused on the hypothalamus and forebrain structures. Individuals that develop seizures associated with hyperactive mTOR in the cerebellum are often resistant to pharmacological intervention and require invasive brain surgery. In severe cases, surgery can fail to control growth and must be repeated. Thus novel treatments are critically needed. Preliminary data show supplemental vitamin D may suppress epilepsy in a mouse model of hyperactive mTOR induced epilepsy and ataxia. This proposal aims to determine whether vitamin D supplementation beginning during adolescence reduces seizures and co- occurring motor impairments (Aim 1A), restores mTOR signaling in adulthood in a rodent model of hyperactive mTOR induced epilepsy and ataxia (Aim 1B) and reverses cerebellar granule cell hypertrophy (Aim 1C). The F99 phase of this fellowship will provide expertise and training in examining the molecular mechanisms underlying genetic causes of neurological disorders and in the testing of novel mechanisms of pharmaceutical therapies. The completion of the F99 phase will provide training that will serve as a springboard for the K00 phase. Baylor University possesses a strong molecular biosciences and imaging core, a dedicated graduate writing center, and faculty and seminars devoted to professional training and teaching. The enclosed proposal for the F99 and K00 phases outlines the training plan for a successful transition from a pre-doctoral trainee to an independent investigator examining treatments for neurodevelopmental disorders.