Semaphorin3d and anomalous pulmonary venous return

描述（由申请人提供）：异常肺静脉回流是一种常见的先天性心脏病，尽管对肺静脉的正常模式知之甚少。信号蛋白是调节轴突和血管排斥信号的引导分子。我们已经产生了两个不同的零等位基因的研究较少的III类信号蛋白，sema3d，这导致异常肺静脉回流。我们的数据表明，sema3d通常起边界作用，限制新生肺静脉内皮的迁移。sema3d的缺失导致肺静脉内皮细胞异位迁移和模式化，导致异常连接。这些发现为异常肺静脉的发育原因提供了一个全新的描述，这需要修订常见的教科书解释。在本提案中，我们将验证sema3d直接与肺静脉内皮细胞结合引起排斥的假设。我们将鉴定功能性sema3d受体和导致排斥的细胞内信号通路，我们将研究sema3d在血管生成过程中如何与Notch和Vegf功能相互作用。

DESCRIPTION (provided by applicant): Anomalous pulmonary venous return is a common form of congenital heart disease though little is known about how the pulmonary veins are normally patterned. Semaphorins are guidance molecules that mediate repulsive cues for axons and blood vessels. We have generated two distinct null alleles of a poorly studied class III semaphorin, sema3d, which results in anomalous pulmonary venous return. Our data suggests that sema3d normally functions as a boundary, constraining migration of nascent pulmonary venous endothelium. The absence of sema3d allows for ectopic migration and patterning of pulmonary venous endothelial cells, leading to anomalous connections. These findings provide an altogether new description of the developmental cause of anomalous pulmonary veins that demands revision of common textbook explanations. In this proposal, we will test the hypothesis that sema3d binds directly to pulmonary venous endothelial cells causing repulsion. We will identify the functional sema3d receptor and the intracellular signaling pathways that result in repulsion, and we will examine how sema3d functionally interacts with Notch and Vegf during angiogenesis.