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

项目总结/摘要 唐氏综合症是人类最普遍的遗传疾病，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号染色体的额外副本，有关生物学机制和非典型出现的详细信息 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

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.