The Role of STRADA in Epileptogenesis and Brain Malformations

STRADA 在癫痫发生和脑畸形中的作用

• 批准号: 10468996
• 负责人: Louis Tuong Chinh Dang
• 金额: $ 17.74万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468996
• 关键词: 3-Dimensional; Acute; Address; Advisory Committees; Affect; Antiepileptogenic; Bioinformatics; Brain; Calcium; Cell Culture Techniques; Cells; Cerebrum; Child; Childhood; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Complex; Cortical Dysplasia; Cortical Malformation; DNA Sequence Alteration; Data; Development; Development Plans; Diffuse; Disease; Doctor of Medicine; Doctor of Philosophy; Educational workshop; Electrophysiology (science); Embryo; Epilepsy; Epileptogenesis; Etiology; FRAP1 gene; Forebrain Development; GABA Agonists; Gene Expression; Gene Expression Profile; Gene Mutation; Genes; Genetic; Genetic Transcription; Goals; Grant; Human; Hyperactivity; Image; Imaging Techniques; Impaired cognition; Induced pluripotent stem cell derived neurons; Intractable Epilepsy; Ion Channel; Journals; Knowledge; Lead; Learning; Link; Measures; Mediating; Mentors; Modeling; Molecular; Morbidity - disease rate; Mutation; Neuroepithelial; Neuroglia; Neurologist; Neuronal Differentiation; Neurons; Neurosciences Research; Neurotransmitter Receptor; Neurotransmitters; Organoids; Other Genetics; Pathogenicity; Pathway interactions; Patients; Pediatric Neurology; Pharmaceutical Preparations; Phenotype; Play; Polyhydramnios, megalencephaly, and symptomatic epilepsy; Process; Program Development; Property; Radial; Research; Research Design; Research Personnel; Research Technics; Rodent; Role; Scientist; Seizures; Sirolimus; Slice; Specimen; Structure; Synapses; Syndrome; Testing; Tissue-Specific Gene Expression; Training; Training Activity; Tuberous Sclerosis; Work; Writing; antagonist; base; brain abnormalities; brain malformation; career; career development; cell type; design; disability; druggable target; experience; field study; gamma-Aminobutyric Acid; hemimegalencephaly; in vitro Model; induced pluripotent stem cell; inhibitor; innovation; insight; loss of function; loss of function mutation; mTORopathies; malformation; medical specialties; meetings; member; mortality; mouse model; multi-electrode arrays; mutant; nerve stem cell; nervous system disorder; neurodevelopment; neurodevelopmental effect; neurogenesis; neuronal excitability; neurophysiology; new therapeutic target; novel; novel therapeutics; patch clamp; prevent; relating to nervous system; response; responsible research conduct; single-cell RNA sequencing; skills; stem cell model; stem cell proliferation; stem cells; targeted treatment; therapeutic target; transcriptomics; translational neuroscience

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.

项目概要 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 转化神经科学领域的独立临床科学家，研究基因突变的机制 导致神经发育异常和癫痫。 申请人：申请人拥有医学博士和博士学位。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。他之前有神经科学研究的经验 使用小鼠模型研究胚胎前脑发育。职业发展计划包括 旨在发展申请人在先进成像技术方面的知识的指导研究期， 电生理学、转录组学和生物信息学。这将大大增强他现有的训练并允许 他将发展成为一名独立调查员。申请人将通过拟议的项目磨练他的科学技能 通过与导师的会面以及与顾问委员会成员的合作进行研究。他会 通过正式课程、期刊俱乐部、实验室会议、研讨会和国家研讨会学习研究技术 会议。培训计划还将包括培养拨款写作技能的研讨会和以下领域的教学培训： 负责任的研究行为。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，影响着 470,000 人 美国的儿童虽然已经开发出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，迄今为止，没有药物可以预防或阻止病情进展 癫痫症。最近，许多癫痫的遗传原因已被确定，提供了对途径的见解 参与癫痫发生。导致 mTOR 通路过度活跃的突变（所谓的“mTORpathies”） 已成为脑畸形和癫痫（包括结节性硬化症）的重要原因 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，由 STRADA 基因纯合性功能丧失引起。该提案将测试 中心假设是，STRADA 的缺失通过促进大脑皮质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，并增加突触神经元过度兴奋。 这项创新提案将使用人类皮质类器官，即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（目标 1）、神经元 兴奋性（目标 2）和细胞类型特异性转录变化（目标 3）。这项研究将提供一个平台 开发机械驱动的疗法，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的癫痫病。

项目成果

STRADA-mutant human cortical organoids model megalencephaly and exhibit delayed neuronal differentiation.

• DOI: 10.1002/dneu.22816
• 发表时间: 2021-07
• 期刊: Developmental neurobiology
• 影响因子: 3
• 作者: Dang LT;Vaid S;Lin G;Swaminathan P;Safran J;Loughman A;Lee M;Glenn T;Majolo F;Crino PB;Parent JM
• 通讯作者: Parent JM