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

维生素 D 对 mTOR 过度活跃诱发癫痫和共济失调小鼠模型中 mTOR 信号传导、癫痫发作和运动行为的影响

• 批准号: 10754319
• 负责人: David Narvaiz
• 金额: $ 4.43万
• 依托单位: BAYLOR UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10754319
• 关键词: Adolescence; Adult; Affect; Age; Antiepileptic Agents; Ataxia; Behavioral; Biological Sciences; Brain; Cell Maintenance; Cerebellum; Confocal Microscopy; DNA Damage; DNA Sequence Alteration; Data; Dedications; Development; Diet; Disease; Educational process of instructing; Electroencephalography; Epilepsy; Equilibrium; FRAP1 gene; Faculty; Failure; Fellowship; Female; First Generation College Students; Foundations; Frequencies; Future; Gait; Genetic; Growth; Hyperactivity; Hypertrophy; Hypothalamic structure; Image; Immunohistochemistry; Impairment; Individual; Intervention; Intractable Epilepsy; Ion Channel Gating; Knockout Mice; Laboratories; Lead; Life; Measures; Mediating; Mentors; Mentorship; Molecular; Motor Activity; Motor Seizures; Mus; Mutation; Neurodevelopmental Disorder; Neurosciences; Operative Surgical Procedures; PTEN gene; Pathologic; Pathway interactions; Patients; Performance; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Pneumonia; Postdoctoral Fellow; Predisposition; Production; Prosencephalon; Proteins; Proto-Oncogene Proteins c-akt; Research; Research Personnel; Research Project Grants; Resistance; Rodent Model; Role; Running; Science; Seizures; Severities; Signal Transduction; Sirolimus; Source; Structure; Techniques; Testing; Tissue Harvesting; Tissues; Training; Transcript; Universities; Upper Respiratory Infections; Video Recording; Vitamin D; Vitamin D supplementation; Western Blotting; Writing; aspirate; autism spectrum disorder; behavior test; brain surgery; career; cell growth; cell motility; comorbidity; design; experience; fortification; gamma-Aminobutyric Acid; granule cell; improved; inhibitor; male; migration; mortality; motor behavior; motor impairment; motor learning; mouse model; nervous system disorder; neuronal excitability; novel; optogenetics; pharmacologic; pre-doctoral; prevent; research faculty; side effect; skills; tenure track; voltage

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.

项目摘要/摘要 哺乳动物靶向雷帕霉素(MTOR)信号的增加是治疗难治性癫痫的已知原因。 MTOR负调控因子的病理性突变导致mTOR信号过度活跃，并已被 在癫痫患者的前脑和小脑中发现。小脑最近被显示出 有助于癫痫的发展。然而，对过度活跃的mTOR诱发癫痫的研究已经 几乎完全集中在下丘脑和前脑结构上。个人发展 与小脑中过度活跃的mTOR相关的癫痫发作通常对药物耐药 而且需要侵入性的脑部手术。在严重的情况下，手术可能无法控制生长，而且必须 重复一遍。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 在过度活跃的mTOR诱导的癫痫和共济失调小鼠模型中抑制癫痫。这项建议旨在 确定从青春期开始补充维生素D是否可以减少癫痫发作和协同作用 发生运动障碍(目标1A)，在多动症啮齿动物模型中恢复成年后的mTOR信号 MTOR可诱导癫痫和共济失调(Aim 1B)并逆转小脑颗粒细胞肥大(Aim 1C)。这个 该奖学金的F99阶段将提供研究分子机制的专业知识和培训。 神经疾病的潜在遗传原因和药物新机制的测试 治疗。F99阶段的完成将提供培训，作为K00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，敬业的毕业生 写作中心，以及致力于专业培训和教学的教师和研讨会。随函附上的建议书 F99和K00阶段概述了从博士前实习生成功过渡到 研究神经发育障碍的治疗方法的独立调查者。