Uncovering functional nodes of the Rett syndrome transcriptome

揭示雷特综合征转录组的功能节点

• 批准号: 10534865
• 负责人: DANIEL CONNOLLY
• 金额: $ 3.43万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534865
• 关键词: Uncovering; functional; nodes; Rett; syndrome

Rett syndrome (RTT) is a severe childhood neurological disorder caused by mutations in the gene encoding Methyl-CpG-Binding Protein 2 (MeCP2). The molecular mechanisms underlying RTT are poorly understood, limiting the development of effective therapies. Loss of MeCP2 leads to widespread changes in gene expression, but it is unclear how these alterations give rise to RTT. This project aims to gain insights into the molecular basis of RTT through the identification of gene expression changes that are consistent across development and shared as a consequence of different RTT-causing MeCP2 mutations. Combining cell typespecific gene expression profiling and functional validation using in vivo CRISPR-based manipulations, these studies will define the molecular features of the RTT transcriptome, improving our understanding of RTT pathogenesis and revealing potentially novel targets for therapeutic development. In addition, this proposal constitutes a comprehensive graduate training plan that includes intellectual and technical research training, training in scientific communication and mentoring, coursework in bioinformatics and statistics, didactics in neuroscience, genetics, and epigenetics, as well as clinical training. Taken together, the studies outlined in this proposal will provide valuable information about the molecular basis of Rett syndrome and provide the applicant a strong training plan that will help him towards achieving his goal of becoming an independent investigator studying the pathogenic mechanisms underlying neurodevelopmental disorders.

Rett综合征(RTT)是一种严重的儿童神经系统疾病，由基因突变引起 编码甲基CpG结合蛋白2(MeCP2)。RTT背后的分子机制很差。 理解，限制了有效疗法的发展。MeCP2的缺失导致了广泛的变化 基因表达，但尚不清楚这些改变是如何引起RTT的。该项目旨在深入了解 RTT的分子基础通过鉴定基因表达的变化是一致的 作为不同RTT引起的MeCP2突变的结果而发展和共享。组合特定的单元格 使用基于体内CRISPR的操作的基因表达谱和功能验证，这些 研究将确定RTT转录组的分子特征，提高我们对RTT的理解 发病机制和揭示潜在的治疗开发的新靶点。此外，这项提案 制定全面的研究生培养计划，其中包括智力和技术研究培训， 科学交流和指导方面的培训，生物信息学和统计学方面的课程， 神经科学、遗传学和表观遗传学，以及临床培训。 综上所述，这项建议中概述的研究将提供关于 Rett综合征的分子基础，并为申请者提供强大的培训计划，帮助他 实现成为研究致病机制的独立调查员的目标 神经发育障碍。