权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Molecular characterization of Hemimegalencephaly

半侧巨脑畸形的分子特征

基本信息

批准号：
8560695
负责人：
JOSEPH G GLEESON
金额：
$ 61.79万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8560695
关键词：
5 year old AKT3 gene Affect Algorithms Alleles Animal Model Bioinformatics Biological Birth Blood Brain Brain imaging Brain region Cell Fraction Cell physiology Cells Cellularity Cerebral cortex Cerebral hemisphere Cerebrum Child Childhood Clinical Codon Nucleotides Cognition Cortical Dysplasia DNA Data Databases Defect Development Disease Electrophysiology (science)Electroporation Epilepsy Evaluation Excision Family history of Focal Dysplasia Gender Gene Mutation Genes Genetic Goals Hemispherectomy Hereditary Disease Histopathology Homeostasis Human Image Immigration Inherited Intellectual functioning disability Intractable Epilepsy Knock-in Mouse Lead Lesion Lobe Malignant Neoplasms Mediating Methodology Methods Microgyria Modeling Molecular Morphology Motor Mus Mutation Mutation Analysis Mutation Detection Neuroanatomy Neurodevelopmental Disorder Neurons Operative Surgical Procedures PIK3CA gene Partial Epilepsies Pathogenesis Pathway interactions Patients Peripheral Pharmaceutical Preparations Phenotype Phosphatidylinositols Pilot Projects Population Proteins Recording of previous events Recruitment Activity Refractory Resected Saliva Sample Size Sampling Severities Severity of illness Signal Transduction Sirolimus Site Somatic Mutation Stem cells Syndrome Testing Tissues Viral Work abstracting base body system burden of illness cohort daughter cell developmental genetics disability disorder subtype exome sequencing gain of function human FRAP1 protein improved in utero inhibitor/antagonist malformation mouse model nervous system disorder neuronal excitability neuropathology next generation sequencing novel programs public health relevance research study

项目摘要

DESCRIPTION (provided by applicant): Molecular characterization of hemimegalencephaly Abstract Somatic mutations, in which a fraction of the cells in the body have a deleterious mutation, is well recognized in cancer but only recently appreciated in neurological disease. In the setting of a somatic mutation in a population of progenitor cells, all daughter cells inherit te mutation and are able to express the resultant phenotype as a function of the differentiation program. We recently identified the first de novo somatic mutations in the developing brain in the condition "hemimegalencephaly", (HME) a catastrophic focal epilepsy condition associated with a malformation of cerebral cortical development (MCD). HME is one of the most severe MCD syndromes, characterized by massive hamartomatous overgrowth of either of the two cerebral hemispheres. Cerebral hemispherectomy is a frequent treatment for the refractory epilepsy, allowing sampling of diseased tissue. By comparing DNA from diseased brain with DNA from blood/saliva, we identified de novo somatic mutations in PIK3CA, AKT3 or MTOR, part of the mTOR pathway. Mutations were present in 8-40% of sequenced alleles in various brain regions sampled during surgery, and some in codons known to activate the protein. However, the pilot study was based on a limited sample size. The goal of this application is to expand upon our initial findings, and elucidate the genetic, developmental, signaling and cell biological mechanisms of HME, particularly in the context of mammalian cortex development. We will combine next-generation sequencing of diseased brain from HME patients with advanced bioinformatics, complete clinical correlated neuroanatomy, and mouse modeling to help advance our understanding of the mechanism of this important disease. We will: 1] Test for de novo somatic mutations in a larger retrospectively and prospectively collected cohort of HME patients. 2] Correlate genetic disease burden with clinical, imaging, and histopathological findings (phenotype). 3] Test how these de novo mutations alter progenitor cell functions in the developing cerebral cortex. The goal of the experiments is to determine how mutations in these genes lead to disrupted cortical development, why these lesions are epileptogenic, and whether repurposing approved medications might benefit patients, with relevance to other focal dysplasias and focal epilepsies.

描述（由申请人提供）：半侧巨脑畸形的分子特征摘要体细胞突变，即体内一部分细胞发生有害突变，在癌症中得到了广泛认可，但最近才在神经系统疾病中得到重视。在祖细胞群体中发生体细胞突变的情况下，所有子细胞都继承了突变，并且能够表达作为分化程序的函数的所得表型。我们最近在“半侧巨脑畸形”（HME）这一与大脑皮质发育（MCD）畸形相关的灾难性局灶性癫痫病的发育中的大脑中发现了第一个从头体细胞突变。HME是最严重的MCD综合征之一，其特征在于两个大脑半球中的任何一个的大量错构瘤过度生长。大脑半球切除术是一种常见的治疗难治性癫痫，允许采样病变组织。通过比较来自患病大脑的DNA与来自血液/唾液的DNA，我们鉴定了PIK 3CA、AKT 3或MTOR（mTOR通路的一部分）中的从头体细胞突变。在手术期间取样的不同脑区中，8-40%的测序等位基因存在突变，一些突变存在于已知激活蛋白质的密码子中。然而，初步研究是基于有限的样本量。本申请的目标是扩展我们的初步发现，并阐明HME的遗传，发育，信号传导和细胞生物学机制，特别是在哺乳动物皮层发育的背景下。我们将联合收割机将HME患者患病大脑的下一代测序与先进的生物信息学、完整的临床相关神经解剖学和小鼠建模相结合，以帮助我们进一步了解这一重要疾病的机制。我们将：1]在更大的回顾性和前瞻性收集的HME患者队列中检测从头体细胞突变。2]将遗传疾病负担与临床、影像学和组织病理学结果（表型）相关联。3]测试这些新生突变如何改变发育中的大脑皮层祖细胞功能。实验的目的是确定这些基因的突变如何导致皮质发育中断，为什么这些病变是致癫痫的，以及重新使用批准的药物是否可能使患者受益，与其他局灶性发育不良和局灶性癫痫相关。