The Role of STRADA in Epileptogenesis and Brain Malformations

STRADA 在癫痫发生和脑畸形中的作用

基本信息

批准号：
10241462
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10241462
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 Megalencephaly 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 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 protein complex Work Writing 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/antagonist 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

项目摘要

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.

项目摘要该建议描述了一项为期五年的职业发展计划，旨在使PI成为职业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学位和博士学位。学位并完成了儿童的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高级成像技术方面的知识的指导研究时期，电生理学，转录组学和生物信息学。这将大大增强他的现有培训，并允许他成长为独立调查员。申请人将通过提议的科学技能通过与他的咨询委员会成员的心理和合作会议进行研究。他会的通过正式的课程，期刊俱乐部，实验室会议，半手赛和国家学习研究技术会议。培训计划还将包括开发赠款写作技巧和教学培训的研讨会负责任的研究行为。这些机会将使申请人能够发展概念和在临床上重要的研究领域中，独立职业所需的技术工具箱。研究计划：癫痫是发病率，死亡率，残疾和费用的主要原因，影响470,000 美国的儿童虽然已经开发了许多控制癫痫的药物，但约有30％的患者不要对药物做出反应，迄今为止，没有任何可以预防或阻止进展的药物癫痫。最近，已经鉴定出许多癫痫病因的遗传原因，为途径提供了见解参与癫痫发生。引起MTOR途径多动症的突变（所谓的“ mtorPathies”）已成为脑畸形和癫痫病的重要原因，包括结节性硬化症复杂的，局灶性皮质发育不良和多氢气，大脑脑和症状癫痫（PMSE）综合征是由Strada基因中纯合功能丧失引起的。该建议将测试中心假设是，Strada的丧失会通过促进A的保留而引起皮质畸形和癫痫神经干细胞的身份，延迟神经元分化以及增加突触神经元过度兴奋性。该创新的建议将使用人类皮质器官，3-D神经结构，类似于发育皮层，确定Strada突变对早期皮质发育的影响（AIM 1），神经元兴奋性（AIM 2）和细胞类型的特定转录变化（AIM 3）。这项研究将为开发机械驱动的疗法，可以停止或反向癫痫发生，以使mtoropathies和我们的调查结果应适用于更广泛的背景下的情节。