Mechanisms of DMP Development and Atrioventricular Septation

房室畸形（AVSD）是一种复杂的心脏畸形，在5%的先天性心脏病患者中发现 冠心病（CHD）。它们在患有遗传疾病如唐氏综合症的患者中特别普遍， 充电综合征。有两种主要类型的AVSD。部分（或不完整）AVSD和完整AVSD。 部分性房室间隔缺损的特征是存在原发性房间隔缺损（pASD）和常见的 AV瓣膜（cAVV），而在完全AVSD中，除了这两种异常，室间隔缺损 室间隔缺损的性质对产后治疗有重要意义。患者 出生时患有完全AVSD的人通常必须在出生后的头几个月内接受手术，以防止 肺动脉高压的发展，而部分AVSD的无症状患者， 手术后的生活患有外科手术修复的AVSD的个人可能需要再次手术来解决， 例如，瓣膜功能不全或起搏器植入，或处理其他干扰 随着年龄的增长，心脏功能也会逐渐恢复。多年来，人们一直认为AVSD是由于 心内膜衍生的AV垫正常发育。这种信念导致了这个词的引入和使用 “内膜垫缺损”。在我们实验室进行的关于背侧间充质前体的作用的研究 (DMP)在心脏发育中的作用已经显著改变了这一模式。第二颗心The Second Heart 场（SHF）衍生的间充质结构位于心脏的静脉极。与AV一起 房室间充质复合体是房室间充质复合体的一部分。 我们最近开始探索Sox 9在AVSD发病机制中的作用。重要的是，我们发现， 来自SHF和来自内皮细胞谱系的Sox 9的缺失均导致完全的AVSD。这一结果促使 我们重新审视，目前的范式的发病机制AVSD。在这个项目中，我们将探讨Sox 9的作用， 在有助于AV间充质复合体的每种间充质结构的发育中， 在pSHF中测试假设，Sox 9是信号通路的常见下游靶点和调节剂 被证明是至关重要的发展的可持续发展。我们还将检验染色体解旋酶- DNA结合蛋白7（Chd 7），在CHARGE综合征患者中经常发现突变的基因， 在pSHF中表达，通过控制pSHF增殖而参与心房发育和AV分隔， 通过调节Sox 9的表达和p53的激活。

Atrioventricular defects (AVSDs) are complex heart malformations found in 5% of patients with congenital heart disease (CHD). They are particularly prevalent in patients with genetic disorders such as Down Syndrome, and CHARGE Syndrome. There are two major types of AVSDs. Partial (or incomplete) AVSDs and complete AVSDs. The partial AVSDs are characterized by the presence of a primary atrial septal defects (pASDs) and a common AV valves (cAVVs), while in complete AVSDs, in addition to these two abnormalities, ventricular septal defects (VSDs) are also found. The nature of an AVSD has a significant implication for postnatal treatment. Patients born with complete AVSDs will typically have to undergo surgery within the first months of life to prevent the development of pulmonary hypertension, whereas asymptomatic patients with partial AVSDs, may receive surgery later in life. Individuals with a surgically repaired AVSD may, at one point, require re-operation to address, for instance, valve insufficiency or pacemaker implantation, or to deal with other conditions that interfere with proper heart function as they get older. For many years it was believed that AVSDs were caused by failure of the endocardially-derived AV cushions to develop properly. This belief led to the introduction and use of the term “endocardial cushion defect”. Studies conducted in our lab on the role of the Dorsal Mesenchymal Protrusion (DMP) in heart development have, however, significantly shifted this paradigm. The DMP is a Second Heart Field (SHF)-derived mesenchymal structure located at the venous pole of the heart. Together with the AV cushions and the mesenchymal cap on the primary atrial septum, the DMP forms the AV mesenchymal complex. We have recently begun to explore the role of Sox9 in AVSD pathogenesis. Importantly, we found that deletion of Sox9 from the SHF and from the endocardial lineage both result in complete AVSD. This result has prompted us to revisit, the current paradigm for the pathogenesis of AVSDs. In this project we will explore the role of Sox9 in the development of each of the mesenchymal structures that contribute to the AV mesenchymal complex and test the hypothesis in the pSHF, Sox9 is a common downstream target and regulator for signaling pathways proven to be critical for development of the DMP. We will also test the hypothesis that chromosome-helicase- DNA-binding protein 7 (Chd7), the gene frequently found to be mutated in patients with CHARGE syndrome and expressed in the pSHF, is involved in DMP development and AV septation by controlling pSHF proliferation and by regulating Sox9 expression and p53 activation.