Gene Expression Networks for Human Cardiac Differentiation in Down Syndrome

项目摘要 这项建议的总体目标是促进对 房室间隔缺损(AVSD)发病风险升高的分子基础 综合征(DS)。房室间隔缺损是一种常见的严重先天性心脏病 (CHD)和DS患者中最常见的CHD形式。房室间隔缺损的发病率 DS患者约为20%，这意味着AVSD风险增加了2000倍 与整倍体种群相比。这种增加的风险还没有得到解释 无论是遗传水平还是发育水平。 这项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 从人诱导的多能干细胞(IPSC)系分化而来的祖细胞。我们 应用房室间隔缺损病理生理学的最新进展推荐一种定向手术入路 探讨DS发生ASVD风险的分子基础。 这项提案的成果将是一组具有潜在潜力的候选基因 DS AVSD风险中的角色。结合我们对分子遗传学的深入了解， 在非DS人群中的AVSD原因，此数据将允许生成特定的和 关于DS AVSD因果关系的可检验假设。拟议的发现是 对于未来识别和询问特定候选基因和 在DS中路径改变是导致房室间隔缺损风险增加的原因。的最终目标是 这项工作增进了对DS中AVSD分子机制的理解， 对AVSD因果关系进行机械解释的可能性。

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.