Mechanisms of DMP Development and Atrioventricular Septation

描述(由申请人提供)：房室间隔缺陷(AVSD)是一种先天性心脏畸形，约占所有先天性心脏病(CHD)患者的5%。它们在唐氏综合征(DS)患者和异位综合征患者中尤其常见。虽然多年来一直认为房室垫发育异常是房室间隔发育异常的唯一机制，但最近的研究表明，位于心脏静脉极的后第二心场(PSHF)组织的扰动，包括初级房间隔和背侧间充质突出(DMP)，在AVSD的发病中也起着关键作用。在这一应用中，我们建议研究参与调控pSHF/DMP发育和房室间隔复合体形成的三个信号通路之间的协同关系，即Hedgehog(HH)信号通路、Wnt(2)/�-catenin通路和BMP信号通路。一些与AVSD发病相关的分子机制也涉及初生纤毛的组装和/或功能，正如我们已经确定的，初生纤毛也存在于pSHF细胞中。纤毛功能和/或结构的异常与aVSD的发病机制有关，结合本研究中概述的一系列观察和初步结果，导致了一个重要的假设，即pSHF中的Wnt/�-catenin和BMP信号通路是协调pSHF发展的复杂分子网络的一部分，位于纤毛相关Shh通路的下游。

DESCRIPTION (provided by applicant): Atrioventricular septal defects (AVSDs) are congenital heart malformations found in approximately 5% of all individuals suffering from congenital heart disease (CHD). They are particularly common in individuals with Down Syndrome (DS) and in patients with heterotaxy syndrome. While it was believed for many years that abnormal development of atrioventricular cushions was the only mechanism involved in the pathogenesis of these defects, more recent studies have revealed that perturbation of tissues derived from the posterior Second Heart Field (pSHF) located at the venous pole of the heart, including the primary atrial septum and the Dorsal Mesenchymal Protrusion (DMP), play a critical role in the pathogenesis of AVSDs as well. In this application we propose to investigate the synergistic relationship between three signaling pathways that are involved in the regulation of pSHF/DMP development and in the formation of the AV septal complex, i.e. the Hedgehog (Hh) signaling pathway, the Wnt(2)/�-catenin pathway, and the BMP signaling pathway. Some of the molecular mechanisms implicated in pathogenesis of AVSDs are also involved in the assembly and/or function of primary cilia, which, as we have established, are also present on pSHF cells. The fact that abnormalities in the function and/or structure of cilia are associated with the pathogenesis of AVSDs, in combination with a series of observations and preliminary results outlined in the proposal, has led to the overarching hypothesis that the Wnt/�-catenin and BMP signaling pathways in the pSHF are part of a complex molecular network orchestrating the development of the pSHF and are located down-stream of the cilia-associated Shh pathway.