Etiology of Congenital Heart Disease in Down Syndrome

描述(申请人提供)：先天性心脏缺陷(CHD)是婴儿发病率和死亡率的主要原因，是一种常见的先天性异常，但对其潜在的遗传基础知之甚少。房室间隔缺陷(AVSD)是唐氏综合征(DS)患者中最常见的先天性心脏病(CHD)，其发生率约为20%。与整倍体人群相比，21三体携带的AVSD风险增加了2000倍，这在遗传或发育水平上都没有得到解释。我们应用DS和AVSD病理生理学的最新进展来解决一个新的假说，即纤毛和声波刺猬(Shh)信号在DS的ASVDS的发生中起重要作用。房室间隔的发展模式最近在莫斯科维茨实验室1-3和其他1-4实验室的工作基础上进行了修订。虽然房室间隔的经典观点是基于心内膜垫的发展，重点是心脏瓣膜，但最近的结果表明，基于纤毛的第二心区(SHF)的Hedgehog信号在这一过程中是必不可少的1-41-4。此外，里夫斯实验室发现，两类胚胎细胞，小脑颗粒细胞前体细胞(GCP)和脑神经脊细胞，在5，6三体小鼠中对Shh的反应减弱。因此，基于纤毛的Hedgehog信号与AVSD有关，在DS细胞中观察到Hedgehog信号的减少。我们将询问这样的假设，即Hedgehog信号和纤毛功能被三体干扰，导致DS小鼠模型中AVSD风险增加。这项工作的最终目的是更好地理解DS中AVSD的发生和发展原因，并有可能更广泛地从机制上阐明AVSD的病因。

DESCRIPTION (provided by applicant): Congenital heart defects (CHD) are a leading cause of morbidity and mortality in infants and comprise a frequent class of congenital anomalies, yet little is known about the underlying genetic basis. Atrioventricular Septal Defects (AVSDs) represent the most common form of Congenital Heart Disease (CHD) in people with Down Syndrome (DS), with AVSD incidence of ca. 20%. Trisomy 21 carries a 2000-fold increased risk for AVSDs compared to the euploid population, which has not been explained at either the genetic or developmental level. We apply recent progress in DS and AVSD pathophysiology to address a novel hypothesis that cilia and sonic hedgehog (Shh) signaling is paramount to the occurrence of ASVDs in DS. The developmental paradigm for atrioventricular septation has undergone recent revision based on work in the Moskowitz laboratory 1-3 and others 1-4. Whereas the canonical view of atrioventricular septation was based on endocardial cushion development with an emphasis on the cardiac valve anlage, recent results demonstrate that cilia-based Hedgehog signaling in the second heart field (SHF) is essential for this process1-41-4. Further, the Reeves lab found that two populations of embryonic cells, cerebellar granule cell precursors (gcp) and cranial neural crest cells, have attenuated response to Shh in trisomic mice 5,6. Thus, cilia-based Hedgehog signaling has been implicated in AVSDs and a Hedgehog signaling decrement has been observed in DS cells. We will interrogate the hypotheses that Hedgehog signaling and cilia function is disrupted by trisomy, resulting in increased AVSD risk in DS mouse models. The ultimate aim of this work is improved understanding of the genetic and developmental causes of AVSDs in DS with the potential to shed mechanistic light on AVSD causation more generally.