Developmental Pathophysiology in Neocortex Caused By Somatic Mutations

体细胞突变引起的新皮质发育病理生理学

基本信息

批准号：
10349538
负责人：
Joseph J LoTurco
金额：
$ 35.22万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
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：
2018-05-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10349538
关键词：
AKT3 gene Affect Animal Model Astrocytes BRAF gene Brain Cells Cerebrum Child Cortical Dysplasia DNA Repair Data Development Dysplasia Electrophysiology (science)Epilepsy Epileptogenesis Functional disorder Ganglioglioma Human Image Impairment Induced Mutation Interneurons Lead Lesion Link MAP Kinase Gene Molecular Mus Mutation Neocortex Neuroglia Neurons PIK3CA gene Partial Epilepsies Pathology Pathway interactions Pattern Pharmacology Phenotype Phosphotransferases Property Proto-Oncogene Proteins B-raf Proto-Oncogene Proteins c-akt Resected Seizures Severities Slice Somatic Mutation Testing Time cellular pathology cohort driver mutation excitatory neuron experimental study gliogenesis human tissue mouse model mutant neocortical nerve stem cell neurogenesis neuronal excitability neuronal tumor novel optogenetics patch clamp prevent progenitor tumor young adult

项目摘要

Every cell has a unique combination of mutations that have accumulated by imperfect DNA repair. If these somatic mutations occur in a critical early time in cerebral cortical development they can affect enough cells in the brain to impair function and result in pathophysiology. Perhaps the best demonstrated examples of somatic mutations causing pathophysiology in the human brain are seizures caused by glial and glial-neuronal tumors and by focal cortical dysplasias. The most common somatic mutations identified to date in these lesions include activating BRAF kinase mutations in approximately 30-50% of resected gangliogliomas, and activating mutations in MTOR, AKT, and PIK3CA kinases in focal cortical dysplasias. Current evidence suggests that these mutations are drivers of the underlying pathologies responsible for focal epilepsies. Consistent with the idea that focal somatic mutations in a subset of neurons and/or glia are sufficient to cause seizures, recent studies have shown that expression of mutations identified in resected human tissue in relatively small numbers of cortical neurons in mice is sufficient to cause seizures. What remains largely unknown is precisely how and whether different somatic mutations lead to neuronal hyperexcitability in cortical neurons and hypersynchrony in cortical circuits. Using novel animal models of focal somatic mutation in neural progenitors we propose to test three hypotheses focused on defining the underlying developmental, cellular and molecular causes of seizures resulting from somatic mutations in cortex: 1) cellular phenotypes and seizure severity are a function of the neocortical progenitors in which epileptogenic mutations arise, 2) elevated cortical excitability is a direct consequence of overactive MAPK/ERK and MTOR pathways in either or both neurons and astrocytes, and 3) epileptiform activity spreads from perilesional zones by altered connections to inhibitory interneuron networks that result in hypersynchronous interneuron activity.

每个细胞都有独特的突变组合，这些突变已不完美地积累 DNA修复。如果这些体细胞突变发生在脑皮质的关键早期开发它们可以影响大脑中足够的细胞以损害功能并导致病理生理学。也许是造成躯体突变的最佳例子人脑中的病理生理是由神经胶质和神经神经神经元肿瘤引起的癫痫发作，通过局灶性皮质发育不良。迄今为止确定的最常见的体细胞突变病变包括大约30-50％切除的BRAF激酶突变在局灶性皮质中，MTOR，AKT和PIK3CA激酶中的神经节和激活突变发育不良。当前的证据表明，这些突变是基础的驱动因素负责局灶性癫痫的病理学。与焦点体细胞的想法一致神经元和/或神经胶质一部分的突变足以引起癫痫发作，最近的研究已经表明，在切除的人组织中鉴定出的突变表达相对较小小鼠中皮质神经元的数量足以引起癫痫发作。什么仍然存在未知是如何以及不同的体细胞突变导致神经元是否导致神经元的未知皮质神经元中的过度兴奋性和皮质回路中的超同步性。使用新型动物神经祖细胞中局灶性体细胞突变的模型我们建议检验三个假设专注于定义癫痫发作的潜在发展，细胞和分子原因皮质中的体细胞突变导致：1）细胞表型和癫痫发作严重程度是一个发生癫痫突变的新皮层祖细胞的功能，2）升高的皮质兴奋性是过度活跃的MAPK/ERK和MTOR的直接结果神经元和星形胶质细胞的途径，以及3）癫痫样活动扩散通过改变连接到抑制性中间神经元网络的连接来从周围区域导致超同步间神经元活性。