Etiology of Congenital Heart Disease in Down Syndrome

描述（由申请人提供）：先天性心脏缺陷（CHD）是婴儿发病和死亡的主要原因，包括常见的一类先天性异常，但对潜在的遗传基础知之甚少。房室间隔缺损（AVSD）是唐氏综合征（DS）患者中最常见的先天性心脏病（CHD），AVSD的发病率约为20%。百分之二十与整倍体人群相比，21三体携带2000倍的AVSD风险，这在遗传或发育水平上都没有解释。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设，即纤毛和音刺猬（Shh）信号传导对DS中ASVD的发生至关重要。 房室间隔的发育范式最近根据Moskowitz实验室1-3和其他实验室1-4的工作进行了修订。尽管房室间隔的经典观点是基于内膜垫的发育，重点是心脏瓣膜原基，但最近的结果表明，第二心脏区域（SHF）中基于纤毛的Hedgehog信号传导对该过程至关重要1 -41-4。此外，Reeves实验室发现，两个胚胎细胞群体，小脑颗粒细胞前体细胞（gcp）和颅神经嵴细胞，对三体小鼠中的Shh反应减弱5，6。因此，基于纤毛的Hedgehog信号转导与AVSD有关，并且在DS细胞中观察到Hedgehog信号转导减少。我们将询问的假设，刺猬信号和纤毛功能被三体性破坏，导致在DS小鼠模型的AVSD风险增加。这项工作的最终目的是加深对DS中AVSD的遗传和发育原因的了解，并有可能更普遍地揭示AVSD因果关系的机制。

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.