Mechanisms of DMP Development and Atrioventricular Septation

DMP 发生和房室间隔的机制

• 批准号: 8903571
• 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: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8903571
• 关键词: Cell Cycle; Cell Proliferation; Cells; Cilia; Complex; Congenital Heart Defects; Defect; Development; Dorsal; Down Syndrome; Endocardial Cushion Defects; Etiology; Event; Failure; Gene Expression; Health; Heart; Heart Atrium; Individual; Knock-out; Lead; Mesenchymal; Modeling; Molecular; Mus; Paper; Pathogenesis; Pathway interactions; Patients; Penetrance; Phenotype; Play; Population; Prevention strategy; Process; Proteins; Regulation; Reporting; Role; Series; Signal Pathway; Signal Transduction; Situs Inversus; Staging; Stream; Structure; Syndrome; Testing; Tissues; Venous; Work; atrioventricular septal defect; bone morphogenetic protein receptors; cell type; congenital heart disorder; insight; mouse model; precursor cell; 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. 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.

描述（由申请人提供）：房室间隔缺损 (AVSD) 是先天性心脏畸形，约 5% 患有先天性心脏病 (CHD)，在唐氏综合症 (DS) 患者和患有先天性心脏病 (CHD) 的患者中尤为常见。虽然多年来人们一直认为房室垫发育异常是导致这些缺陷的唯一机制，但最近的研究表明，扰动是导致这些缺陷的唯一机制。源自位于心脏静脉极的后第二心野 (pSHF) 的组织，包括原发性房间隔和背侧间质突起 (DMP)，在 AVSD 的发病机制中也发挥着关键作用。我们建议研究参与 pSHF/DMP 发育调节和 AV 间隔复合体（即 Hedgehog）形成的三种信号通路之间的协同关系(Hh) 信号通路、Wnt(2)/β-连环蛋白通路和 BMP 信号通路与 AVSD 发病机制有关的一些分子机制也涉及初级纤毛的组装和/或功能。我们已经确定，纤毛功能和/或结构的异常与 AVSD 的发病机制相关，这一事实与提案中概述的一系列观察和初步结果相结合。总体假设是 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，并且位于纤毛相关 Shh 通路的下游。