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。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pSHF/pSHF发育调节和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-连环蛋白信号传导途径和BMP信号传导途径。AVSD发病机制中涉及的一些分子机制也涉及初级纤毛的组装和/或功能，正如我们已经建立的，初级纤毛也存在于pSHF细胞上。纤毛功能和/或结构异常与AVSD的发病机制相关，结合提案中概述的一系列观察结果和初步结果，导致了一个总体假设，即pSHF中的Wnt/β-连环蛋白和BMP信号通路是协调pSHF发育的复杂分子网络的一部分，并且位于纤毛的下游。相关的Shh通路。

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.