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。房间隔缺损可分为两种亚型：“不完全型”房间隔缺损，分流局限于房间隔缺损口(PASD)；“完全型”房间隔缺损伴房室和室间隔分流(通过入口型VSD)。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。此外，我们还将研究初级纤毛在SHF中的作用，因为CIIA的功能和/或结构异常与AVSD的发病有关。这两个AIM之间的协同作用是因为AIM 1中研究的与AVSD发病相关的分子机制也涉及初生纤毛的组装和/或功能。最后，使用一些条件性基因敲除模型，我们旨在获得“不完全”与“完全”AVSD发病机制上的差异的见解，检验在所有形式的AVSD中发现的PASD完全是DMP发育扰动的结果的假设，而房室垫和心室心肌中的额外异常发育事件是存在于室水平和房室瓣膜中的缺陷的原因。

 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. Two AVSD subtypes can be distinguished; "incomplete" AVSDs, where shunting is restricted to the atrial level via an ostium primum atrial septal defect (pASD) and "complete" AVSDs with shunting at atrial as well as ventricular level (via an inlet type VSD). 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)/ß-catenin pathway, and the BMP signaling pathway. In addition, we will study the role of primary cilia in the SHF, as abnormalities in the function and/or structure of ciia are associated with the pathogenesis of AVSDs. The synergy between the two aims is found in the fact that the molecular mechanisms implicated in pathogenesis of AVSDs investigated in aim 1 are also involved in the assembly and/or function of primary cilia. Finally, using a number of conditional knock out models we aim at obtaining insights into the differences in the pathogenesis of "incomplete" vs "complete" AVSDs, testing the hypothesis that the pASD found in all forms of AVSDs exclusively results from perturbation of DMP development, while additional abnormal developmental events in the AV cushions and ventricular myocardium are responsible for the defects present at ventricular level and in the AV valves.