Mechanisms of DMP Development and Atrioventricular Septation

 描述（由申请人提供）：房室间隔缺损（AVSD）是一种先天性心脏畸形，在所有患有先天性心脏病（CHD）的个体中约有5%。它们在唐氏综合征（DS）和内脏异位综合征患者中特别常见。可区分两种AVSD亚型：“不完全”AVSD，其中分流通过原发性房间隔缺损（pASD）限制在心房水平;“完全”AVSD，在心房和心室水平（通过入口型VSD）分流。虽然多年来人们认为房室垫的异常发育是这些缺陷的发病机制中涉及的唯一机制，但最近的研究表明，来自位于心脏静脉极的后第二心野（pSHF）的组织的扰动，包括初级房间隔和背侧间充质前叶（PSV），在AVSD的发病机制中也起着关键作用。在本申请中，我们提出研究参与调节pSHF/pSHF发育和AV隔复合体形成的三种信号传导途径之间的协同关系，即Hedgehog（Hh）信号传导途径、Wnt（2）/β-连环蛋白途径和BMP信号传导途径。此外，我们将研究初级纤毛在SHF中的作用，因为纤毛的功能和/或结构异常与AVSD的发病机制有关。这两个目标之间的协同作用被发现在目标1中研究的AVSD发病机制中涉及的分子机制也涉及初级纤毛的组装和/或功能。最后，使用许多条件性敲除模型，我们旨在深入了解“不完全”与“完全”AVSD发病机制的差异，检验在所有形式的AVSD中发现的pASD完全由AVSD发育的扰动引起的假设，而AV垫和心室心肌中的额外异常发育事件是导致心室水平和房室瓣。

 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.