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Cortical development and pathogenesis in DEPDC5-related epilepsies

DEPDC5 相关癫痫的皮质发育和发病机制

基本信息

批准号：
10164883
负责人：
Yu Wang
金额：
$ 40.86万
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：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10164883
关键词：
Amino Acids Animal Model Animals Architecture Brain Brain Diseases Brain region Cells Child Communities Contralateral Cortical Dysplasia Cortical Malformation Data Development Dorsal Dysplasia Electroencephalogram Electrophysiology (science)Electroporation Epilepsy Etiology Event FRAP1 gene Fingerprint Focal Seizure Frequencies Gene Mutation Genes Genetic Hippocampus (Brain)Human In Vitro Interneurons Intractable Epilepsy Knock-out Lesion Lysosomes Megalencephaly Modeling Molecular Molecular Genetics Monitor Mutagenesis Mutation Neuroglia Operative Surgical Procedures Partial Epilepsies Pathogenesis Pathologic Pathology Pathway interactions Patients Periodicity Phenotype Prefrontal Cortex Research Research Proposals Resected Rodent Model Role Seizures Site Somatic Mutation TSC1 gene Thalamic structure Tissues Transgenic Animals Tuberous sclerosis protein complex astrogliosis clinically relevant conditional knockout effective therapy excitatory neuron gene therapy glial cell development hemimegalencephaly in utero insight knockout animal mutant neurodevelopment next generation sequencing novel novel strategies polypeptide prevent progenitor recruit response tool

项目摘要

ABSTRACT Focal cortical dysplasia (FCD) is the most common underlying pathology in children with drug resistant epilepsies. DEPDC5 mutations have been increasingly recognized as the most important genetic cause in focal epilepsies with or without FCD. Using focal somatic mutagenesis approaches, we recently generated a rodent model with pathological and electrographic signatures that are highly clinically-relevant to human FCD. However, precisely how dysplastic cortex and seizures arise from Depdc5 mutation remains unknown. We propose to focus on defining the underlying genetic, cellular and circuitry mechanisms contributing to DEPDC5-related epilepsies as well as establishing the critical roles of DEPDC5 in cortical development. We will provide conceptual insights broadly relevant to understanding mTOR-related malformation of cortical development and epilepsies. Our central hypothesis is that DEPDC5 mutations in cortical progenitors generate focal intrinsic epileptogenecity through its critical roles in sculpting neural and glial development, and that inhibition of mTORC1 recruitment will restore cytoarchitectures and suppress seizures.

摘要局灶性皮质发育不良（FCD）是耐药儿童中最常见的潜在病理学，癫痫DEPDC5突变已越来越被认为是最重要的遗传原因，局灶性癫痫伴或不伴FCD。使用焦点体细胞诱变方法，我们最近产生了一个啮齿类动物模型的病理学和电图特征与人类FCD高度临床相关。然而，究竟发育不良的皮质和癫痫发作是如何由Depdc 5突变引起的仍然未知。我们我建议把重点放在定义潜在的遗传，细胞和电路机制，有助于 DEPDC5相关癫痫以及建立DEPDC5在皮质发育中的关键作用。我们将提供与理解mTOR相关的皮质畸形广泛相关的概念性见解发展和癫痫。我们的中心假设是，皮质祖细胞中的DEPDC 5突变产生通过其在塑造神经和神经胶质发育中的关键作用，抑制mTORC 1募集将恢复细胞结构并抑制癫痫发作。