Trisomy 21 Model Atlas

项目摘要。 唐氏综合征（DS），由21三体（T21）引起的遗传疾病，是最常见的染色体异常。 异常和智力和发育残疾的主要原因。T21影响发育和/或 几乎每个器官系统的功能，使DS患者易患许多并发症， 如老年痴呆症、先天性心脏病和自身免疫性疾病等。虽然 虽然T21导致了基因表达程序的全基因组失调，但人们对T21是如何引起的却知之甚少。 T21影响不同组织和器官的基因表达，以及这些影响如何促成病因 DS的并发症。因此，显然需要了解复杂的因果关系 T21、改变的基因表达与器官发育和病理生理学之间的关系。 几种DS小鼠模型概括了DS的关键表型，并已用于研究基因表达 DS中的失调。此外，诱导多能干细胞（iPSC）系统已被用于研究细胞内的细胞因子。 T21在人类细胞中的作用因此，在明确回应融资机会公告PAR- 22-247，我们在此提出产生组织特异性鼠和人的21三体模型图谱 转录组，匹配器官发育和结构的详细指标。使用小鼠 模型将提供对组织和发育阶段特异性转录组变化的见解， 病理生理学，而从iPSC分化的人类细胞类型将剖析T21和T22的细胞内在特征。 验证小鼠模型的发现。我们的具体目标是： 1.生成跨模型系统受21三体影响的基因表达程序图谱。 在强有力的初步数据的支持下，我们建议在这里完成十个转录组变化的图谱， 在小鼠的三个发育阶段的器官和来自iPSC衍生的人类细胞类型的匹配数据。 2.在细胞水平上明确21三体对器官发育和病理生理的影响。到 为了研究基因表达失调和组织功能障碍之间的联系，我们将评估器官 通过组织病理学分析，多重免疫荧光成像， 单细胞RNA测序，以及来源于iPSC的人类器官的表征。 3.通过INCLUDE数据中心管理、组织和共享所有开放访问的数据。我们将确保 通过完成仔细的文件管理，所有数据都可以在INCLUDE数据中心公开获取， 组织、开发元数据模式和创建代码存储库。这将确保地图集 成为一种持久的资源，可以在本补助金的范围之外使用。 总之，这一资源将促进我们对T21对器官发育的影响的理解， 病理学，同时使研究结果在小鼠模型和人类细胞类型中交叉验证。

PROJECT SUMMARY. Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), is the most prevalent chromosomal abnormality and a leading cause of intellectual and developmental disability. T21 affects the development and/or function of nearly every organ system, predisposing individuals with DS to many co-occurring conditions such as Alzheimer’s disease, congenital heart defects, and autoimmune disorders, among others. Although it is accepted that T21 causes genome-wide dysregulation of gene expression programs, little is known about how T21 affects gene expression across different tissues and organs, and how these effects contribute to the etiology of the co-occurring conditions of DS. Therefore, there is a clear need to understand the complex cause-effect relationships between T21, altered gene expression, and organ development and pathophysiology. Several mouse models of DS recapitulate key phenotypes of DS and have been used to study gene expression dysregulation in DS. Additionally, induced pluripotent stem cell (iPSC) systems have been employed to study the effects of T21 in human cell types. Therefore, in clear response to the Funding Opportunity Announcement PAR- 22-247, we propose here to generate a Trisomy 21 Model Atlas of tissue-specific murine and human transcriptomes, matched to detailed metrics of organ development and architecture. The use of mouse models will provide insights into tissue- and developmental stage-specific transcriptome changes and pathophysiology, while human cell types differentiated from iPSCs will dissect cell-intrinsic features of T21 and validate findings from the mouse models. Our Specific Aims are: 1. Generate an atlas of gene expression programs affected by trisomy 21 across model systems. Supported by strong preliminary data, we propose here to complete an atlas of transcriptome changes in ten organs across three developmental stages in mice and matched data from human cell types derived from iPSCs. 2. Define the impact of trisomy 21 on organ development and pathophysiology at the cellular level. To investigate the link between dysregulated gene expression and tissue dysfunction, we will assess organ development and pathophysiology through histopathological profiling, multiplexed immunofluorescence imaging, single-cell RNA-sequencing, and characterization of human organoids derived from iPSCs. 3. Curate, organize, and share all data for open access through the INCLUDE Data Hub. We will ensure that all data is made publicly available in the INCLUDE Data Hub by completing careful file curation and organization, developing a metadata schema, and creating a code repository. This will ensure that the atlas becomes a lasting resource that can be used beyond the scope of this grant. Altogether, this resource will advance our understanding of the effects of T21 on organ development and pathology, while enabling findings cross-validated in mouse models and human cell types.