Gene Expression Networks for Human Cardiac Differentiation in Down Syndrome

唐氏综合症人类心脏分化的基因表达网络

• 批准号: 10057128
• 负责人: Ivan Paul Moskowitz
• 金额: $ 15.6万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057128
• 关键词: Attenuated; Bioinformatics; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cell Line; Cells; Cilia; Data; Data Set; Defect; Development; Differentiated Gene; Down Syndrome; Erinaceidae; Etiology; Fibroblasts; Functional disorder; Future; Gene Expression; Gene Expression Profiling; Generations; Genes; Genetic; Goals; Heart; Human; Incidence; Investigation; Kinetics; Knowledge; Light; Modeling; Molecular; Molecular Genetics; Mus; Pathway interactions; Population; Research Personnel; Risk; Role; Translating; Work; atrioventricular septal defect; base; congenital heart disorder; differential expression; heart disease risk; human pluripotent stem cell; improved; induced pluripotent stem cell; mouse model; progenitor; response; smoothened signaling pathway; stem cell differentiation; stem cells; transcription factor; transcriptome; transcriptome sequencing

Project Summary The overall goal of this proposal is to contribute to the understanding of the molecular basis for the elevated risk of Atrioventricular Septal Defects (AVSDs) in Down syndrome (DS). AVSDs are a common serious form of Congenital Heart Disease (CHD) and the most common form of CHD in people with DS. AVSD incidence in people with DS is approximately 20%, representing 2000-fold increased AVSD risk compared to the euploid population. This increased risk has not been explained at either the genetic or developmental level. The specific goals of this proposal are to investigate the differentiation and gene expression differences between Down syndrome and isogenic control cardiomyocyte progenitors, differentiated from human induced Pluripotent Stem Cell (iPSC) lines. We apply recent progress in AVSD pathophysiology to nominate a directed approach for investigating the molecular basis of ASVD risk in DS. The deliverables of this proposal will be a set of candidate genes with potential roles in DS AVSD risk. Combined with our deep knowledge of the molecular genetics of AVSD causation in the non-DS population, this data will allow generation of specific and testable hypotheses concerning DS AVSD causation. The proposed discovery are essential for future efforts to identify and interrogate specific candidate genes and pathways altered in DS and responsible for increased AVSD risk. The ultimate aim of this work is improved understanding of the molecular mechanisms of AVSDs in DS, with the potential to shed mechanistic light on AVSD causation.

项目摘要 本提案的总体目标是促进对《公约》的理解， 唐氏症房室间隔缺损（AVSD）风险升高的分子基础 综合征（DS）。AVSD是一种常见的严重形式的先天性心脏病 (CHD)也是DS患者中最常见的冠心病AVSD发病率 患有DS的人约为20%，代表AVSD风险增加2000倍 与整倍体群体相比。这种增加的风险尚未解释， 无论是基因层面还是发育层面。 该建议的具体目标是研究分化和基因 唐氏综合征与同基因对照心肌细胞的表达差异 在一些实施方案中，细胞是从人诱导的多能干细胞（iPSC）系分化的祖细胞。我们 应用AVSD病理生理学的最新进展，为 研究DS中ASVD风险的分子基础。 该提案的可交付成果将是一组具有潜力的候选基因 在DS AVSD风险中的作用。结合我们对基因组分子遗传学的深入了解， 非DS人群中的AVSD因果关系，该数据将允许生成特定和 关于DS AVSD因果关系的可检验假设。提出的发现是 对于未来识别和询问特定候选基因的工作至关重要， 在DS中改变的通路和负责增加AVSD风险。的最终目的 这项工作提高了对DS中AVSD分子机制的理解， 揭示室间隔缺损病因的机制的可能性。