Genetic and transcriptomic profiling of the epileptic network in patients with surgically treated seizures

手术治疗癫痫患者癫痫网络的遗传和转录组学分析

• 批准号: 10663374
• 负责人: Adam Lawrence Numis
• 金额: $ 20.19万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10663374
• 关键词: Affect; Anticonvulsants; Award; Biological Markers; Biological Sciences; Blood; Brain; Brain region; Catalogs; Cell Nucleus; Cells; Child; Childhood; Clinical; Collaborations; Cortical Malformation; DNA Sequence Alteration; Data; Data Set; Development; Diagnosis; Diagnostic; Disease; Electrodes; Electroencephalography; Enrollment; Epilepsy; Epileptogenesis; Excision; Freedom; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genomics; Germ-Line Mutation; Goals; Harvest; Inflammatory; Institution; Intractable Epilepsy; Investigation; Lead; Lesion; Link; Maps; Medical; Molecular; Mutation; Neurotransmitters; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Persons; Pharmaceutical Preparations; Population; Procedures; Process; Resected; Resistance; Seizures; Somatic Mutation; Source; Technology; Tissue-Specific Gene Expression; Tissues; Whole Blood; brain surgery; brain tissue; cohort; exome sequencing; genetic profiling; improved; minimally invasive; nano-string; neuroimaging; neurophysiology; next generation sequencing; novel; participant enrollment; precision medicine; programs; single-cell RNA sequencing; success; therapeutic target; transcriptome sequencing; transcriptomic profiling; transcriptomics; young adult

PROJECT SUMMARY Medically-refractory epilepsy affects nearly 1 in 300 people, and for these patients resective brain surgery may be the only change for seizure freedom. Patients with abnormal neuroimaging findings which correlate with abnormal electroencephalography (EEG) activity have the best chance of seizure freedom after epilepsy surgery. In patients without clear neuroimaging abnormalities, stereo-EEG (sEEG) can localize an epileptic lesion and increase the success of a future resective surgery. sEEG is a minimally invasive procedure where electrodes are placed throughout, and within the brain to identify the seizure onset zone, peri-epileptic network and nonepileptic brain regions. After sEEG electrode removal, adherent cells can be used to evaluate genomic material in order to better understand the molecular processes that define an epileptic network. The overall objective of this application is to understand the mechanisms in the development of intractable epilepsy with the goal of developing a precision medicine approach to therapy. We will evaluate the genetics and transcriptomics of brain tissue resected in children and young adults with intractable epilepsy undergoing sEEG followed by resective surgery. Our central hypothesis that patients who develop intractable epilepsy have 1) somatic mutations in epilepsy-related molecular pathways which are not present in the germline and 2) unique gene expression profiles will be identified in epileptic tissue with dysregulation of known neurotransmitter and inflammatory pathways, compared to peri-epileptic and non-epileptic brain tissue.

项目概要 医学上难治性癫痫影响近三百人中就有一人，对于这些患者，脑部切除手术可能 是实现无癫痫发作的唯一改变。神经影像学检查结果异常的患者 脑电图 (EEG) 活动异常是癫痫患者摆脱癫痫发作的最佳机会 外科手术。对于没有明显神经影像学异常的患者，立体脑电图 (sEEG) 可以定位癫痫病灶 病变并增加未来切除手术的成功率。 sEEG 是一种微创手术，其中 电极放置在大脑各处和内部，以识别癫痫发作区、癫痫周围网络 和非癫痫脑区。去除 sEEG 电极后，贴壁细胞可用于评估基因组 材料，以便更好地理解定义癫痫网络的分子过程。整体 本应用的目的是了解难治性癫痫的发展机制 开发精准医学治疗方法的目标。我们将评估遗传学和 患有顽固性癫痫的儿童和年轻人切除的脑组织的转录组学 sEEG 随后进行切除手术。我们的中心假设是患有顽固性癫痫的患者 1) 癫痫相关分子途径中存在体细胞突变，但种系中不存在这种突变； 2）将在癫痫组织中鉴定出独特的基因表达谱，并调节失调 与癫痫周围和非癫痫脑组织相比，已知的神经递质和炎症途径。