Trisomy 21 Model Atlas

21 三体模型图谱

• 批准号: 10769002
• 负责人: Joaquin M. Espinosa
• 金额: $ 73.68万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10769002
• 关键词: Address; Adult; Affect; Alzheimer' s Disease; Architecture; Atlases; Autoimmune Diseases; Biological Models; Blood; Bone Marrow; Brain; Cells; Chromosome 21; Chromosome abnormality; Clinical; Code; Communities; Complex; Congenital Heart Defects; Data; Data Set; Defect; Development; Down Syndrome; Embryo; Ensure; Etiology; Functional disorder; Funding Opportunities; Gene Dosage; Gene Expression; Genes; Genetic Diseases; Grant; Heart; Hematoxylin and Eosin Staining Method; Heterogeneity; Human; Human Chromosomes; Image; Immune system; Immunofluorescence Immunologic; Individual; Intellectual functioning disability; Intestines; Kidney; Knowledge; Link; Liver; Lung; Mediating; Metadata; Modeling; Mus; Muscle; Newborn Infant; Organ; Organoids; Pathology; Persons; Phenotype; Population; Protocols documentation; Research; Research Personnel; Resources; Respiratory Tract Infections; Sampling; Skin Tissue; Stains; System; Time; Tissue atlas; Tissue-Specific Gene Expression; Tissues; Trisomy; Validation; Work; body system; cell type; data hub; differentiation protocol; genome-wide; human data; improved; induced pluripotent stem cell; insight; mouse model; open data; organ growth; programs; repository; response; single-cell RNA sequencing; stem cell differentiation; transcriptome; transcriptome sequencing

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.

项目摘要。 唐氏综合症（DS）是由21（T21）引起的遗传病，是最普遍的染色体 异常和智力和发育障碍的主要原因。 T21影响开发和/或 几乎每个器官系统的功能，诱使具有DS的个体易于使用，以达到许多同时发生的条件 作为阿尔茨海默氏病，先天性心脏缺陷和自身免疫性疾病等。虽然是 接受T21引起基因表达程序的全基因组失调，对如何如何了解 T21影响不同组织和器官之间的基因表达，这些影响如何促进病因 DS的同时存在条件。因此，明确需要了解复杂的原因效应 T21，基因表达改变，器官发育与病理生理学之间的关系。 DS的几种小鼠模型概括了DS的关键表型，并已用于研究基因表达 DS中的失调。此外，已聘请了诱导的多能干细胞（IPSC）系统来研究 T21在人类细胞类型中的影响。因此，明确回应了资金机会公告 22-247，我们在这里提议生成一个21模型的组织特异性鼠和人地图集 转录组，符合器官开发和建筑的详细指标。鼠标的使用 模型将提供有关组织和开发特定阶段的转录组变化的见解， 病理生理学，而与IPSC区分的人类细胞类型会剖析T21和 从鼠标模型中验证发现。我们的具体目的是： 1。生成一个模型系统中三体构造的基因表达程序的地图集。 在强大的初步数据的支持下，我们在这里建议完成十个转录组变化的地图集 小鼠三个发育阶段的器官以及来自IPSC的人类细胞类型的数据匹配。 2。定义了三体性21对细胞水平的器官发育和病理生理的影响。到 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，多重免疫荧光成像的发育和病理生理学， 单细胞RNA测序以及源自IPSC的人类器官的表征。 3.策展人，组织并共享所有数据，以通过Include Data Hub开放访问。我们将确保 通过完成仔细的文件策划和 组织，开发元数据模式以及创建代码存储库。这将确保地图集 成为持久的资源，可以超出这笔赠款的范围。 总的来说，该资源将促进我们对T21对器官开发和器官开发的影响的理解 病理学，同时可以在小鼠模型和人类细胞类型中进行交叉验证。