Determining the neurodevelopmental cell type specific regulatory networks impacted in Down syndrome

确定唐氏综合症影响的神经发育细胞类型特异性调节网络

• 批准号: 10595260
• 负责人: Kimberly Anne Aldinger
• 金额: $ 9.83万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10595260
• 关键词: Address; Atlases; Benchmarking; Biological; Biological Models; Brain; Cell Nucleus; Cells; Chromatin; Chromosome 21; Data; Data Set; Development; Disease; Down Syndrome; Funding; Future; Gene Expression; Genetic Diseases; Goals; Human; Impaired cognition; Intellectual functioning disability; Knowledge; Maps; Molecular; Molecular Abnormality; Neurons; Pathway Analysis; Phenotype; Regulation; Research; Resolution; Severities; Tissues; brain tissue; cell type; clinical phenotype; functional genomics; gene regulatory network; multiple omics; neuropathology; parent grant; single-cell RNA sequencing; transcriptome

ABSTRACT Abstract of the funded parent grant: Down syndrome is the most prevalent genetic condition in humans and a major cause of intellectual disability. Although the severity and extent of phenotypes present in Down syndrome partially result from an extra copy of chromosome 21, details regarding the biological mechanisms and the emergence of atypical development are not understood. To address this significant gap in knowledge, we previously created a ‘Developmental Cell Atlas of Down Syndrome’ by using single-cell RNA-sequencing to profile the transcriptomes of over 700,000 cells derived from multiple tissues. This proposal represents our ongoing efforts to characterize the molecular and cellular identity of cellular phenotypes present in the developing brain in Down syndrome. In Aim 1, we will map the Down syndrome cells onto a reference framework of the developing human brain by pooling existing single-cell RNA-sequencing data. In Aim 2, we will use our established human brain functional genomics pipeline to infer cell-type-specific gene regulatory networks altered in Down syndrome. Leveraging existing data, this study will provide critical information about the emergence and regulation of early brain development in Down syndrome that can be used to elucidate the molecular mechanisms underlying early neuropathology and to benchmark model systems for disease relevant neuronal phenotypes. Abstract of the requested supplement: This application is being submitted for PA-20-272 in accordance with NOT-OD-21-076. The goal of this research supplement is to experimentally validate the findings from our cell- type specific gene regulatory network analysis using high resolution chromatin mapping. We propose to use single cell chromatin mapping in control and trisomy 21 developing brain tissue. We will integrate these new data with our existing single-nucleus gene expression data to confirm the gene regulatory networks predicted via our human brain functional genomics pipeline. Successful completion of the supplementary aims will define gene regulatory networks that are perturbed in Down syndrome brain development and form the basis of future studies aimed at elucidating the cellular and molecular consequences that precede clinical phenotypes.

摘要 摘要资助父母补助金：唐氏综合症是人类最普遍的遗传疾病， 智力残疾的主要原因。尽管唐氏症中存在的表型的严重程度和程度 综合征部分原因是21号染色体的额外拷贝，关于生物机制的细节 和非典型发育的出现是不了解的。为了弥补这一重大知识差距， 我们之前通过使用单细胞RNA测序创建了一个“唐氏综合征发育细胞图谱”， 对来自多种组织的70多万个细胞的转录组进行分析。这份提案代表了我们 目前正在努力表征存在于细胞表型的分子和细胞特性， 唐氏综合症的大脑发育在目标1中，我们将唐氏综合征细胞映射到参考上， 通过汇集现有的单细胞RNA测序数据，构建了人类大脑发育的框架。在目标2中， 将使用我们建立的人脑功能基因组学管道来推断细胞类型特异性基因调控 唐氏综合症的神经网络改变利用现有数据，本研究将提供以下方面的关键信息： 唐氏综合征早期大脑发育的出现和调节，可用于阐明 作为早期神经病理学基础的分子机制，并用于疾病相关的基准模型系统 神经元表型 要求补充的摘要：本申请是根据PA-20-272提交的， NOT-OD-21-076。本研究补充的目标是通过实验验证我们细胞的发现- 型特异性基因调控网络分析使用高分辨率染色质作图。我们建议使用 对照组和21三体发育脑组织中的单细胞染色质图谱。我们将整合这些新的 数据与我们现有的单核基因表达数据，以证实预测的基因调控网络 通过我们的人脑功能基因组学管道。成功完成补充目标将定义 基因调控网络在唐氏综合症大脑发育中受到干扰，并形成未来的基础。 旨在阐明临床表型之前的细胞和分子结果的研究。