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 三体 (T21) 引起的遗传病，是最常见的染色体疾病 T21 异常是智力和发育障碍的主要原因，影响发育和/或。 几乎每个器官系统的功能都受到影响，使 DS 患者容易出现许多同时发生的情况，例如 例如阿尔茨海默病、先天性心脏病和自身免疫性疾病等。 人们普遍认为 T21 会导致基因表达程序的全基因组失调，但我们对如何导致基因表达程序失调知之甚少 T21 影响不同组织和器官的基因表达，以及这些影响如何影响病因学 因此，明确需要了解 DS 的复杂因果关系。 T21、改变的基因表达以及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 此外，诱导多能干细胞（iPSC）系统已被用来研究 DS 的失调。 因此，明确响应融资机会公告 PAR- 22-247，我们在此建议生成组织特异性小鼠和人类的 21 三体模型图谱 转录组，与小鼠器官发育和结构的详细指标相匹配。 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 分化而来的人类细胞类型将剖析 T21 和 验证小鼠模型的结果是： 1. 跨模型系统生成受 21 三体性影响的基因表达程序图谱。 在强有力的初步数据的支持下，我们在此建议在十年内完成转录组变化图谱 小鼠体内三个发育阶段的器官以及来自 iPSC 的人类细胞类型的匹配数据。 2. 在细胞水平上定义 21 三体对器官发育和病理生理学的影响。 研究失调的基因表达与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、多重免疫荧光成像研究发育和病理生理学， 单细胞 RNA 测序以及源自 iPSC 的人类类器官的表征。 3. 通过 INCLUDE 数据中心管理、组织和共享所有数据以供开放访问。 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 组织、开发元数据模式并创建代码存储库，这将确保图集。 成为一种持久资源，可以在本次拨款的范围之外使用。 总而言之，该资源将增进我们对 T21 对器官发育和 病理学，同时能够在小鼠模型和人类细胞类型中交叉验证研究结果。