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：
10624357
负责人：
Yu Wang
金额：
$ 42.2万
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 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624357
关键词：
Alleles Amino Acids Animal Model Animals Architecture Brain Brain Diseases Brain region Cells Child Communities Contralateral Cortical Dysplasia Cortical Malformation Data Development Dorsal Dysplasia Electroencephalography Electrophysiology (science)Electroporation Epilepsy Etiology Event FRAP1 gene Fingerprint Focal Seizure Frequencies Gene Mutation Genes Genetic Hippocampus Human In Vitro Interneurons Intractable Epilepsy Knock-out Lysosomes Megalencephaly Modeling Molecular Molecular Genetics Monitor Mutagenesis Mutation Neuroglia Operative Surgical Procedures Partial Epilepsies Pathogenesis Pathologic Pathology Pathway interactions Patients Periodicals Periodicity Phenotype Prefrontal Cortex Research Research Proposals Resected Rodent Model Role Seizures Site Somatic Mutation Thalamic structure Tissues Transgenic Animals Tuberous Sclerosis astrogliosis clinically relevant conditional knockout effective therapy epileptiform excitatory neuron gene therapy glial cell development hemimegalencephaly in utero insight knockout animal mutant neurodevelopment neuropathology 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.

抽象的局灶性皮质发育不良（FCD）是耐药性儿童中最常见的基本病理癫痫病。 DEPDC5突变越来越被认为是最重要的遗传原因有或没有FCD的焦点癫痫。使用局灶性体细胞诱变方法，我们最近生成了啮齿动物模型具有与人FCD相关的病理和电学特征。然而，恰恰是如何由DEPDC5突变引起的发育不良皮质和癫痫发作。我们建议专注于定义有助于与DEPDC5相关的癫痫以及确定DEPDC5在皮质发育中的关键作用。我们将提供与理解与MTOR相关的皮质畸形广泛相关的概念见解发展和癫痫。我们的中心假设是皮质祖细胞中的DEPDC5突变会产生通过其在雕刻神经和神经胶质发育中的关键作用，局部癫痫遗传学性质，并抑制MTORC1募集将恢复细胞结构并抑制癫痫发作。