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

项目摘要/摘要 唐氏综合症是人类最常见的遗传疾病，也是导致智力低下的主要原因 残疾。尽管唐氏综合征的表型严重程度和程度部分是由于 一份额外的21号染色体的拷贝，关于生物机制和非典型肺炎的出现的细节 发展是不被理解的。为了解决这一重大的知识差距，我们以前创建了一个 应用单细胞RNA测序技术绘制唐氏综合征发育细胞图谱 来自多个组织的超过700,000个细胞的转录本。这份提案代表了我们正在进行的 研究大脑发育过程中细胞表型的分子和细胞特性的努力 患有唐氏综合症。在目标1中，我们将把唐氏综合症细胞映射到 通过汇集现有的单细胞RNA测序数据来开发人脑。在目标2中，我们将使用我们的 建立人脑功能基因组学管道推断特定细胞类型的基因调控网络 在唐氏综合症中发生改变。利用现有数据，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 早期神经病理基础的分子机制和相关疾病的基准模型系统 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.