Mechanisms of DMP Development and Atrioventricular Septation

DMP 发生和房室间隔的机制

• 批准号: 8885266
• 负责人: Arno Wessels
• 金额: $ 37.38万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8885266
• 关键词: Alleles; Atrial Heart Septal Defects; Candidate Disease Gene; Cell Cycle; Cell physiology; Cells; Cilia; Complex; Congenital Heart Defects; Data; Defect; Development; Dorsal; Down Syndrome; Endocardial Cushion Defects; Erinaceidae; Etiology; Event; Failure; Gene Expression; Heart; Heart Atrium; Individual; Inhibition of Cell Proliferation; Knock-out; Lead; Left; Mesenchymal; Modeling; Molecular; Mus; Mutate; Myocardium; Paper; Pathogenesis; Pathway interactions; Patients; Penetrance; Play; Population; Prevention strategy; Process; Proteins; Regulation; Reporting; Role; Series; Side; Signal Pathway; Signal Transduction; Situs Inversus; Smith-Lemli-Opitz Syndrome; Sonic Hedgehog Pathway; Specimen; Staging; Stream; Structure; Syndrome; Testing; Tissues; Venous; Ventricular; Ventricular Septal Defects; Work; atrioventricular septal defect; base; beta catenin; bone morphogenetic protein receptors; congenital heart disorder; insight; mouse model; mutant; precursor cell; public health relevance; research study; smoothened signaling pathway

 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.

 描述（由适用提供）：大约5％患有先天性心脏病（CHD）的人中，大约5％的人发现了先天性的心脏畸形（AVSD）。它们在唐氏综合症（DS）和异努综合症患者的患者中尤为常见。可以区分两个AVSD亚型； “不完整”的AVSD，其中shhunting被限制在心房中的ostium primum心房间隔缺陷（PASD）和“完整” AVSD，并在心房和心室水平（通过Inlet Type VSD）分流。 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 AVSD也是如此。在此应用中，我们建议研究PSHF/DMP开发的三个信号传导途径之间的协同关系，以及在AV中隔综合体的形成中，即HEDGEHOG（HH）信号通路，Wnt（2）/ß-catenin途径以及BMP信号通路。此外，我们将研究原发性纤毛在SHF中的作用，因为CIIA功能和/或结构中的异常与AVSD的发病机理有关。这两个目标之间的协同作用是在AIM 1中研究的AVSD发病机理中实施的分子机制也参与了原发性纤毛的组装和/或功能。最后，使用许多有条件的敲除模型，我们旨在获得对“不完整”与“完整” AVSD的发病机理差异的见解，检验了以下假说：在各种形式的AVSD中发现的PASD在AVSD中发现的PASD在DMP开发中造成的各种形式，而DMP的开发却是在Av Cush cush and Interrium defect中呈现出额外的异常发育事件，该事件是刻板的。阀。