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。脑信号蛋白是介导轴突和血管排斥信号的导向分子。我们已经产生了两个不同的无效等位基因的研究不足的第三类信号蛋白，sema3d，导致肺静脉回流异常。我们的数据表明，sema3d通常作为一个边界，限制新生肺静脉内皮细胞的迁移。sema3d的缺失使得肺静脉内皮细胞异位迁移和形成模式，导致异常连接。这些发现提供了一个全新的描述异常肺静脉的发展原因，需要修改常见的教科书解释。在这个提议中，我们将检验sema3d直接与肺静脉内皮细胞结合引起排斥的假设。我们将确定功能sema3d受体和细胞内信号通路，导致排斥，我们将研究如何sema3d功能与Notch和VEGF在血管生成过程中相互作用。

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.