Creation of a Schwann Cell Gene Regulatory Network

雪旺细胞基因调控网络的创建

• 批准号: 10581647
• 负责人: John P Svaren
• 金额: $ 18.11万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581647
• 关键词: Affect; Binding; Binding Sites; Bioinformatics; Cell Differentiation process; ChIP-seq; Charcot-Marie-Tooth Disease; Code; Collaborations; Complex; Computer Models; Data; Data Set; Development; Disease; EGR2 gene; Enhancers; Gene Expression Regulation; Gene Mutation; Genes; Genetic; Genetic Transcription; Genotype-Tissue Expression Project; Goals; Hereditary Disease; Heritability; Homeostasis; Human; Human Genome; Individual; Laboratories; Link; Maintenance; Minority; Modeling; Molecular; Mutation; Myelin; Myelin Sheath; NR4A1 gene; Nerve; Nervous System; Neural Crest; Neuropathy; Pathway interactions; Patients; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Peripheral nerve injury; Predictive Value; Process; Publishing; Regulatory Element; Resolution; Resources; Role; Schwann Cells; Signal Transduction; Site; Testing; Untranslated RNA; Variant; cell type; computational pipelines; epigenomics; gene regulatory network; genetic disorder diagnosis; genetic variant; genome sequencing; improved; in vivo; loss of function; myelination; nervous system development; nervous system disorder; network models; programs; tool; transcription factor; transcription regulatory network; whole genome

Abstract. The peripheral neuropathy known as Charcot-Marie-Tooth Disease (CMT1A) is one of the most common heritable disorders in the nervous system, affecting 1 in 2500 individuals. Tremendous progress has been made in identifying structural and coding variants that cause this disease, with over 100 genes having mutations associated with CMT. However, a substantial number of individuals do not have a definitive genetic diagnosis. The goal of this project is to develop a comprehensive Schwann cell gene regulatory network model incorporating experimental data on peripheral nerve with ChIP-seq analyses of TF binding as well as epigenomic annotations from human peripheral nerve that have recently become available. The model will incorporate data showing the dynamics of Schwann cell enhancers that have been shown to become dynamically regulated after peripheral nerve injury. Moreover, the model will be validated in its ability to identify key regulatory elements using eQTL analysis. Development of a Schwann cell network model with sufficient resolution to determine effects on individual enhancers and TF binding sites will be developed for eventual application to WGS analysis of patient data with peripheral neuropathy, including not only CMT but also other disorders affecting the peripheral nervous system.

抽象的。被称为夏科-玛丽-图斯病(CMT1A)的周围神经病变 是神经系统中最常见的遗传性疾病之一，影响1/4 2500人。在确定结构和结构方面取得了巨大进展 导致这种疾病的编码变异，有100多个基因发生突变 与CMT关联。然而，相当数量的人没有 明确的基因诊断。这个项目的目标是开发一个全面的 结合实验数据的雪旺细胞基因调控网络模型 周围神经转铁蛋白结合及表观基因组的芯片序列分析 来自人类周围神经的注释，最近已经可以使用。这个 模型将包含显示雪旺细胞增强剂动态的数据，这些细胞增强剂具有 在周围神经损伤后被证明是动态调节的。此外， 该模型将在使用eQTL识别关键调控因素的能力方面进行验证 分析。具有足够分辨率的雪旺细胞网络模型的发展 确定对单个增强剂和转铁蛋白结合位点的影响将为 最终应用于周围神经病患者数据的WGS分析， 不仅包括肌萎缩侧索硬化症，还包括其他影响周围神经系统的疾病。