Hedgehog signaling during cardiovascular patterning in the mouse

小鼠心血管模式中的刺猬信号传导

• 批准号: 7567524
• 负责人: JOHN A KLINGENSMITH
• 金额: $ 39万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7567524
• 关键词: Adult; Affect; Anterior; Cardiac; Cardiovascular system; Cells; Complex; Congenital Heart Defects; Data; Defect; Development; Double Outlet Right Ventricle; Embryo; Embryonic Heart; Endocardium; Endoderm; Erinaceidae; Excision; Heart; In Vitro; Ligands; Mesenchymal; Mitral Valve; Molecular; Mus; Myocardial; Myocardium; Neural Crest Cell; Pattern; Persistent Truncus Arteriosus; Population; Pulmonary artery structure; Research Personnel; Right ventricular structure; SHH gene; Signal Pathway; Signal Transduction; Staging; Testing; Tissues; Tricuspid valve structure; Ventricular; cardiogenesis; congenital heart disorder; genetic manipulation; human SMO protein; in vivo; insight; malformation; mutant; precursor cell; programs; receptor; research study; smoothened signaling pathway

DESCRIPTION (provided by applicant): The outflow tract of the embryonic heart contributes to the formation of the aortic and pulmonary artery. Defects in outflow tract development result in severe congenital heart defects such as persistent truncus arteriosus and double outlet right ventricle. Similarly, atrio-ventricular (A-V) cushions contribute to the formation of the mitral and tricuspid valves as well as to the septa of the adult heart. Abnormalities in A-V cushion development can result in severe congenital heart defects such as A-V canal or tricuspid and mitral valve atresias. Understanding how the outflow tract forms and the A-V cushions develop is therefore critical to understanding the development of many congenital heart defects. Classic studies have demonstrated the requirement of cardiac neural crest cells (CNCC) in the septation of the single outflow tract into the aortic and pulmonary arteries. More recent studies have provided new insight into the development of the myocardium of the outflow tract of the heart. These studies demonstrate the existence of heart precursor cells that are added to the outflow tract and right ventricle. Our preliminary data suggests that the Shh signaling pathway is critical for these "anterior heart field" (AHF) cells as well as for migratory CNCC during outflow tract formation and septation. In addition, Shh appears to be required for A-V cushion formation and therefore valve development. Loss of the Shh signal results in a single outflow tract (pulmonary artery atresia) and a single A-V valve. We propose that the cardiac defects seen in Shh mutants are due to abnormal development of both CNCC and the AHF during outflow tract development as well as abnormal endocardial cushion formation during valve formation. We propose examining the cell autonomous requirement for hedgehog signaling within AHF and CNCC in the coordinated development of the outflow tract using a Cre/LoxP approach. Similarly we will test the cell autonomous requirement of hedgehog signaling during A-V valve formation using genetic manipulations in the mouse.

描述（由申请人提供）：胚胎心脏的流出道有助于主动脉和肺动脉的形成。流出道发育缺陷会导致严重的先天性心脏病，如持续性动脉干和右心室双出口。同样，房室 (A-V) 垫有助于二尖瓣和三尖瓣以及成人心脏隔膜的形成。房室垫发育异常可能导致严重的先天性心脏病，例如房室管或三尖瓣和二尖瓣闭锁。因此，了解流出道的形成和 A-V 垫的形成对于了解许多先天性心脏缺陷的发展至关重要。经典研究表明，在分隔主动脉和肺动脉的单个流出道时需要心脏神经嵴细胞（CNCC）。最近的研究为心脏流出道心肌的发育提供了新的见解。这些研究证明了心脏前体细胞的存在，这些细胞被添加到流出道和右心室。我们的初步数据表明，Shh 信号通路对于这些“前心区”(AHF) 细胞以及流出道形成和分隔过程中的迁移性 CNCC 至关重要。此外，Shh 似乎是 A-V 缓冲垫形成以及瓣膜发育所必需的。 Shh 信号的丢失会导致单个流出道（肺动脉闭锁）和单个 A-V 瓣膜。我们认为，Shh 突变体中出现的心脏缺陷是由于流出道发育过程中 CNCC 和 AHF 的异常发育以及瓣膜形成过程中心内膜垫形成的异常所致。我们建议使用 Cre/LoxP 方法检查 AHF 和 CNCC 中流出道协调发展中刺猬信号的细胞自主需求。同样，我们将使用小鼠的遗传操作来测试 A-V 瓣形成过程中刺猬信号传导的细胞自主需求。