Molecular characterization of Hemimegalencephaly

半侧巨脑畸形的分子特征

• 批准号: 9444701
• 负责人: JOSEPH G GLEESON
• 金额: $ 59.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9444701
• 关键词: 5 year old; AKT3 gene; Affect; Algorithms; Alleles; Animal Model; Bioinformatics; Biological; Birth; Blood; Brain; Brain Diseases; 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; Defect; Development; Disease; Electrophysiology (science); Electroporation; Epilepsy; Evaluation; Excision; FRAP1 gene; Family history of; Focal Dysplasia; Gender; Gene Mutation; Genes; Genetic; Goals; Hemispherectomy; Hereditary Disease; Histopathology; Homeostasis; Human; Image; Inherited; Intellectual functioning disability; Intractable Epilepsy; Knock-in; Lead; Lesion; Lobe; Malignant Neoplasms; Mediating; Medical; 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; base; body system; burden of illness; clinical imaging; cohort; daughter cell; disability; disorder subtype; exome; exome sequencing; experimental study; gain of function; improved; in utero; inhibitor/antagonist; malformation; migration; mouse model; nervous system disorder; neuronal excitability; neuropathology; next generation sequencing; novel; programs; prospective; public health relevance

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）：半巨脑畸形的分子表征 摘要 体细胞突变（体内的一部分细胞具有有害突变）在癌症中得到了充分认识，但最近才在神经系统疾病中得到认识。在祖细胞群体发生体细胞突变的情况下，所有子细胞都会遗传突变，并且能够根据分化程序表达所得表型。我们最近在“半巨脑畸形”（HME）中发现了发育中大脑中的第一个从头体细胞突变，这是一种与大脑皮质发育畸形（MCD）相关的灾难性局灶性癫痫病。 HME 是最严重的 MCD 综合征之一，其特征是两个大脑半球中任一半球的大量错构瘤过度生长。大脑半球切除术是治疗难治性癫痫的常用方法，可以对患病组织进行取样。通过将患病大脑的 DNA 与血液/唾液中的 DNA 进行比较，我们发现了 PIK3CA、AKT3 或 MTOR（mTOR 通路的一部分）中的新生体细胞突变。手术期间采样的各个大脑区域中 8-40% 的已测序等位基因中存在突变，其中一些突变存在于已知激活蛋白质的密码子中。然而，该试点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质发育的背景下。我们将把 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模型相结合，以帮助加深我们对这一重要疾病机制的理解。我们将： 1] 在更大的回顾性和前瞻性收集的 HME 患者队列中测试新生体细胞突变。 2] 将遗传病负担与临床、影像学和组织病理学结果（表型）相关联。 3] 测试这些从头突变如何改变发育中的大脑皮层中的祖细胞功能。实验的目的是确定这些基因的突变如何导致皮质发育紊乱，为什么这些病变会导致癫痫，以及重新利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。

项目成果

Shared HLA Class I and II Alleles and Clonally Restricted Public and Private Brain-Infiltrating αβ T Cells in a Cohort of Rasmussen Encephalitis Surgery Patients.

• DOI: 10.3389/fimmu.2016.00608
• 发表时间: 2016
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Dandekar S;Wijesuriya H;Geiger T;Hamm D;Mathern GW;Owens GC
• 通讯作者: Owens GC

Evidence for Resident Memory T Cells in Rasmussen Encephalitis.

拉斯穆森脑炎中常驻记忆 T 细胞的证据。

• DOI: 10.3389/fimmu.2016.00064
• 发表时间: 2016
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Owens,GeoffreyC;Chang,JuliaW;Huynh,MyN;Chirwa,Thabiso;Vinters,HarryV;Mathern,GaryW
• 通讯作者: Mathern,GaryW