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，是一类常见的先天性异常，但对其潜在的遗传基础知之甚少。房室间隔缺损（AVSDs）是唐氏综合征（DS）患者中最常见的先天性心脏病（CHD）形式，AVSD的发病率约为20%。与整倍体人群相比，21三体人群患AVSDs的风险增加了2000倍，这在遗传或发育水平上都没有得到解释。我们利用最近在DS和AVSD病理生理学方面的进展来解决一个新的假设，即纤毛和sonic hedgehog （Shh）信号在DS中asvd的发生中起着至关重要的作用。最近，基于莫斯科维茨实验室1-3和其他实验室1-4的工作，房室分隔的发展范式经历了修订。虽然房室分隔的典型观点是基于心内膜缓冲的发展，并强调心脏瓣膜，但最近的研究结果表明，第二心场（SHF）中基于纤毛的刺猬信号对于这一过程至关重要1-41。此外，Reeves实验室还发现，在三体小鼠中，两种胚胎细胞——小脑颗粒细胞前体（gcp）和颅神经嵴细胞——对Shh的反应减弱。因此，基于纤毛的Hedgehog信号通路与AVSDs有关，并且在DS细胞中观察到Hedgehog信号通路的减少。我们将质疑Hedgehog信号和纤毛功能被三体性破坏的假设，从而导致DS小鼠模型中AVSD风险增加。这项工作的最终目的是提高对DS中AVSD的遗传和发育原因的理解，并有可能更普遍地揭示AVSD病因的机制。

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.