Deciphering brain mosaicism in drug-resistant epilepsy at cellular resolution

在细胞分辨率下解读耐药性癫痫中的大脑镶嵌现象

• 批准号: 10841995
• 负责人: Tracy Ann Bedrosian
• 金额: $ 3.34万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10841995
• 关键词: Acute; Address; Administrative Supplement; Adult; Behavior; Behavioral; Brain; Cells; Child; Childhood; Chromatin; Cognition; Cognitive; Communication; Data; Development; Epigenetic Process; Epilepsy; Exhibits; Genetic Transcription; Goals; Hippocampus; Individual; Intellectual functioning disability; Intractable Epilepsy; Knowledge; Life; Link; Longitudinal Studies; Maps; Mentorship; Molecular; Mosaicism; Pharmaceutical Preparations; Research; Research Training; Resolution; Risk; Seizures; Techniques; Training; behavior test; career; cell type; early experience; epigenomics; innovation; long-term sequelae; mouse model; multiple omics; novel strategies; parent project; pre-doctoral; programs; response; skills; transcriptomics

Project Summary This administrative supplement will provide a predoctoral research training and mentorship program for Ms. Sydney Townsend under the parent project R01NS129784 entitled “Deciphering brain mosaicism in drug- resistant epilepsy at cellular resolution.” Ms. Townsend’s goal is to study the long-term consequences of pediatric drug-resistant epilepsy, while developing her own analytical skills with a focus on single-cell transcriptomic and epigenomic data. Early-life seizures, particularly those that are difficult to control with medication, have profound consequences for brain development and function later in life. Up to half of children with epilepsy exhibit intellectual disability and long-term deficits in communication, cognition, and behavior. Therefore, it is a critical need to understand how early-life seizures alter brain development to develop treatment opportunities. Epilepsy has been linked to transcriptional and epigenetic remodeling in the adult brain, but a major barrier to understanding its developmental effects has been dissecting the acute vs. long-lasting contributions of individual cell types. Understanding both acute and long-lasting molecular responses to early-life epilepsy on a cellular level would inform the mechanisms through which long-term cognitive and behavioral deficits arise. This application aims to bridge this gap in knowledge by using cutting-edge single-cell multiomics techniques to investigate epigenetic and transcriptional changes in developing hippocampal cells following early-life seizures using a mouse model. The second aim will map long-lasting molecular changes to hippocampal-dependent behavioral consequences. The central hypothesis is that early-life seizures have long-lasting cell-type-specific effects on transcription and chromatin accessibility that may account for the long-term cognitive and behavioral effects. The rationale for this project is that understanding these changes will ultimately present new treatment opportunities. The research proposed in this supplement application is highly innovative because it takes a new approach to understanding the long-term sequalae of early-life seizures by leveraging leading-edge advances in single-cell multiomics. The research aligns with the aims of the parent project by examining molecular and functional effects of early-life epilepsy at cellular resolution, while addressing career training goals for Ms. Townsend and promoting diversity in scientific research.

项目摘要 这种行政补充剂将为女士提供一项专业研究培训和攻向计划。 父母项目R01NS129784的悉尼汤森（Sydney Townsend 汤森女士的目标是研究小儿的长期后果 耐药性癫痫，同时发展自己的分析技能，重点是单细胞转录组和 表观基因组数据。早期癫痫发作，尤其是那些难以控制药物的癫痫发作， 后来生活中大脑发育和功能的后果。多达一半的患有癫痫的儿童 智力残疾和沟通，认知和行为的长期防御。因此，这是一个关键 需要了解早期癫痫发作如何改变脑发育为发展治疗机会。癫痫 与成人大脑中的转录和表观遗传重塑有关，但是 了解其发育效果一直在剖析个人的急性和长期贡献 细胞类型。了解急性和持久分子对细胞上早期癫痫的反应 级别将为长期认知和行为定义的机制提供信息。 应用程序旨在通过使用尖端的单细胞多组学技术来弥合知识中的这一差距 研究早期癫痫发作后，研究海马细胞发育中的表观遗传和转录变化 使用鼠标模型。第二个目标将绘制持久的分子变化与海马依赖性 行为后果。中心假设是早期癫痫发作具有持久的细胞类型特异性 可能解释长期认知和行为的转录和染色质可及性的影响 效果。该项目的理由是了解这些变化最终将提出新的治疗方法 机会。该补充应用中提出的研究具有很高的创新性，因为它采用了新的 通过利用领先的进步来理解早期癫痫发作的长期序列 在单细胞多组合中。该研究通过检查分子和 早期癫痫在细胞分辨率上的功能影响，同时解决女士的职业培训目标。 汤森德并促进科学研究的多样性。