Semaphorin3d and anomalous pulmonary venous return

描述(由申请人提供)：肺静脉异常回流是先天性心脏病的一种常见形式，尽管人们对肺静脉的正常形态知之甚少。信号素是引导分子，为轴突和血管传递排斥信号。我们已经产生了研究很少的III类信号素Sema3d的两个截然不同的零等位基因，这会导致异常的肺静脉返流。我们的数据表明，Sema3d通常作为边界发挥作用，限制新生肺静脉内皮细胞的迁移。Sema3d的缺失允许肺静脉内皮细胞异位迁移和构型，导致异常连接。这些发现对异常肺静脉的发育原因提供了一个全新的描述，需要修改常见的教科书解释。在这项提议中，我们将检验Sema3d直接与肺静脉内皮细胞结合导致排斥的假设。我们将确定功能上的Sema3d受体和导致排斥的细胞内信号通路，并将研究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.