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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.

项目总结/摘要唐氏综合症是人类最普遍的遗传性疾病，也是智力低下的主要原因残疾。虽然唐氏综合征中存在的表型的严重程度和程度部分是由于 21号染色体的额外拷贝，关于生物机制和非典型性的出现的细节，发展不被理解。为了解决这一重大知识差距，我们以前创建了一个 “唐氏综合征发育细胞图谱”，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。这份提案代表了我们正在进行的努力表征发育中的大脑中存在的细胞表型的分子和细胞特性唐氏综合症在目标1中，我们将唐氏综合征细胞映射到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，我们将使用建立人脑功能基因组学管道，推断细胞类型特异性基因调控网络在唐氏综合症中发生了改变利用现有的数据，这项研究将提供有关唐氏综合征早期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