The Role of STRADA in Epileptogenesis and Brain Malformations

项目摘要 该提案描述了一个为期五年的职业发展计划，旨在引导PI成为一名 翻译神经科学的独立临床科学家，研究基因突变的机制 导致神经发育异常和癫痫。 申请人：申请人持有医学博士学位。和博士学位，并已完成儿童专业培训 神经病学以及癫痫/临床神经生理学。他以前有神经科学研究的经验 利用小鼠模型研究胚胎前脑的发育。职业发展计划包括： 一段时间的指导研究，旨在发展申请人在先进成像技术的知识， 电生理学、转录组学和生物信息学。这将大大提高他现有的训练，并允许 让他成为一名独立的调查员。申请人将通过拟议的 他通过与导师的会议以及与顾问委员会成员的合作进行研究。他将 通过正式的课程学习研究技术，期刊俱乐部，实验室会议，研讨会和国家 会议.培训计划还将包括举办讲习班，以发展赠款撰写技能和以下方面的教学培训： 负责任地进行研究。这些机会将使申请人能够发展概念和 在临床重要研究领域的独立职业所需的技术工具箱。 研究计划：癫痫是发病、死亡、残疾和费用的主要原因，影响470，000人 虽然已经开发了许多控制癫痫发作的药物，但大约30%的患者 对药物没有反应，到目前为止，没有药物可以预防或阻止进展 癫痫的症状最近，许多癫痫的遗传原因已被确定，提供了对途径的见解 与癫痫发生有关导致mTOR通路过度活跃的突变（所谓的"mTOR病"） 已经成为脑畸形和癫痫的重要原因，包括结节性硬化症 复杂、局灶性皮质发育不良、羊水过多、巨脑畸形和症状性癫痫（PMSE） 综合征，其由STRADA基因中的纯合功能丧失引起。这项提案将考验 中心假说认为，STRADA的丢失通过促进大脑皮层神经元的保留而导致皮质畸形和癫痫。 神经干细胞身份、延迟神经元分化和增加突触神经元过度兴奋性。 这项创新的提议将使用人类皮质类器官，类似于发育中的大脑的3D神经结构。 皮质，以确定STRADA突变对早期皮质发育的影响（目的1），神经元 兴奋性（Aim 2）和细胞类型特异性转录变化（Aim 3）。本研究将提供一个平台， 开发机械驱动的治疗方法，可以阻止或逆转mTORopathies的癫痫发生，我们的 研究结果应适用于更广泛背景下的癫痫。

Project Summary This proposal describes a five-year career development program designed to lead the PI to a career as an independent clinician scientist in translational neuroscience, studying mechanisms by which genetic mutations result in abnormal neurodevelopment and epilepsy. Applicant: The applicant holds M.D. and Ph.D. degrees and has completed specialty training in Child Neurology as well as Epilepsy/Clinical Neurophysiology. He has previous experience in neuroscience research using mouse models to study embryonic forebrain development. The career development plan includes a period of mentored research designed to develop the applicant's knowledge in advanced imaging techniques, electrophysiology, transcriptomics, and bioinformatics. This will greatly enhance his existing training and allow him to develop as an independent investigator. The applicant will hone his scientific skills through the proposed research by meetings with his mentor and collaborations with the members of his advisory committee. He will learn research techniques through formal coursework, journal clubs, lab meetings, seminars, and national meetings. The training plan will also include workshops to develop grant writing skills and didactic training in the responsible conduct of research. These opportunities will allow the applicant to develop the conceptual and technical toolbox needed for an independent career in a clinically important field of study. Research Plan: Epilepsy is a major cause of morbidity, mortality, disability, and expense, and affects 470,000 children in the U.S. While many medications to control seizures have been developed, about 30% of patients do not respond to medications, and to date, there are no medications that can prevent or halt the progression of epilepsy. Recently, many genetic causes of epilepsy have been identified, providing insights into pathways involved in epileptogenesis. Mutations causing hyperactivity of the mTOR pathway (so-called “mTORpathies”) have emerged as an important cause of cerebral malformations and epilepsy, including tuberous sclerosis complex, focal cortical dysplasia, and polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE) syndrome, which is caused by a homozygous loss-of-function in the STRADA gene. This proposal will test the central hypothesis that loss of STRADA causes cortical malformation and epilepsy by promoting retention of a neural stem cell identity, delaying neuronal differentiation, and increasing synaptic neuronal hyperexcitability. This innovative proposal will use human cortical organoids, 3-D neural structures that resemble the developing cortex, to determine the effect of STRADA mutations on early cortical development (Aim 1), neuronal excitability (Aim 2), and cell-type specific transcriptional changes (Aim 3). This study will provide a platform to develop mechanistically driven therapies that can halt or reverse epileptogenesis for mTORopathies, and our findings should be applicable to epilepsies in a broader context.