Mechanisms of DMP Development and Atrioventricular Septation

房室缺陷(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 疾病(CHD)。它们在患有唐氏综合症等遗传性疾病的患者中尤其普遍，而且 冲锋综合症。AVSD主要有两种类型。部分(或不完全)AVSD和完整AVSD。 部分房间隔缺损的特征是存在原发性房间隔缺损(PASD)和常见的房间隔缺损 房室瓣(CAVV)，而在完全性房室间隔缺损中，除了这两种异常外，还有室间隔缺陷 (VSD)也被发现。房室间隔缺损的性质对出生后的治疗有重要意义。病人 患有完全性房室间隔缺损的新生儿通常必须在出生后的头几个月内接受手术，以防止 发展为肺动脉高压，而无症状的部分房室间隔缺损患者可能会 在以后的生活中做手术。接受手术修复的房室间隔缺损患者可能需要再次手术来解决， 例如，瓣膜关闭不全或植入起搏器，或处理其他干扰 随着年龄的增长，他们的心脏功能也会正常。多年来，人们认为AVSD是由故障引起的 心内膜衍生的房室垫正常发育。这一信念导致了这一术语的引入和使用 “心内膜垫缺陷”。本实验室对背侧间充质突起作用的研究 然而，心脏发育中的(DMP)显著改变了这一范式。DMP是第二颗心脏 场(SHF)来源的间充质结构位于心脏的静脉极。与反病毒一起使用 DMP在初级房间隔的垫层和间充质帽之间形成房室间充质复合体。 我们最近开始探索Sox9在AVSD发病机制中的作用。重要的是，我们发现这个删除 来自SHF和心内膜血统的SOX9均可导致完全性房室间隔缺损。这一结果促使 我们要重新审视目前AVSD发病机制的范式。在本项目中，我们将探讨Sox9的作用 在构成房室间充质复合体的每一种间充质结构的发育过程中， 在pSHF中测试假设，Sox9是信号通路的常见下游靶标和调节因子 事实证明，这对DMP的发展至关重要。我们还将测试染色体解旋酶- DNA结合蛋白7(CHD7)，该基因在Charge综合征和 在pSHF中表达，通过控制pSHF的增殖，参与DMP的形成和房室间隔的形成 通过调节Sox9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.