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

基本信息

批准号：
10304101
负责人：
Kimberly Anne Aldinger
金额：
$ 36.61万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
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/10304101
关键词：
Address Age Atlases Benchmarking Bioinformatics Biological Biological Models Birth Brain Cell Fraction Cell Nucleus Cells Chromosome 21 Computing Methodologies Data Data Pooling Data Set Development Disease Down Syndrome Enhancers Exhibits Fetal Development Funding Future Gene Expression Gene Expression Profile Genes Genetic Genetic Diseases Genomics Goals Human Impaired cognition Intellectual functioning disability Knowledge Lead Link Maps Methods Modeling Molecular Molecular Abnormality Neurodevelopmental Disorder Neurons Phenotype Population Study Process Regulation Regulator Genes Sampling Severities Small Nuclear RNA Testing Therapeutic Tissue Donors Tissues United States National Institutes of Health Variant Work base cell type cost data resource experimental study fetal functional genomics genomic data mind control molecular marker molecular phenotype multiple omics nerve stem cell neurodevelopment neuropathology prenatal sex single-cell RNA sequencing therapeutic target transcription factor transcriptome transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT 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 is 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.

项目概要/摘要唐氏综合症是人类最普遍的遗传病，也是智力低下的主要原因尽管唐氏综合症表现型的严重程度和范围部分是由于。 21 号染色体的额外副本，有关生物学机制和非典型染色体出现的详细信息为了解决这一知识上的重大差距，我们之前创建了一个 “唐氏综合症发育细胞图谱”通过使用单细胞 RNA 测序来分析来自多种组织的超过 700,000 个细胞的转录组代表了我们正在进行的研究。表征发育中大脑中存在的细胞表型的分子和细胞识别工作在目标 1 中，我们将把唐氏综合症细胞映射到一个参考框架上。通过汇集现有的单细胞 RNA 测序数据来开发人类大脑在目标 2 中，我们将使用我们的研究成果。建立人脑功能基因组学管道来推断细胞类型特异性基因调控网络利用现有数据，这项研究将提供有关唐氏综合症的重要信息。唐氏综合症早期大脑发育的出现和调节可用于阐明早期神经病理学的分子机制以及疾病相关的基准模型系统神经元表型。