Role of NFAT in the vascular endothelium

钙调神经磷酸酶-NFAT信号通路参与了人体内许多重要的过程。特别是，我们知道很多关于这一途径在免疫系统中扮演的关键角色，它在免疫系统中开启和关闭许多关键基因。然而，人们对它在身体其他部位的作用知之甚少。我对了解血管形成的控制很感兴趣。这项工作的重点是内皮细胞，它构成了所有血管的内层，也是血管形成的第一部分。当NFAT信号被抑制时，血管不能正确形成。我们最近检查了内皮细胞中失去NFAT信号的小鼠胚胎，发现它们的动脉健康，但静脉有缺陷。动脉将富含氧气的血液输送到毛细血管，而静脉则将血液返回心脏。虽然已经知道静脉内皮细胞与动脉内皮细胞有很大的不同，但我们不知道静脉形成和生长是如何调节的。基于对NFAT突变胚胎中静脉没有正确形成的观察，我们观察了NFAT蛋白NFATc1的结合模式。这表明NFATc1直接与静脉形成所需的许多基因的增强子(开-关开关)结合，这表明NFAT信号可能直接开启这些基因。在该项目中，我们将分析NFAT信号有缺陷的小鼠和斑马鱼胚胎，以确定为什么静脉不能正常形成。我们还将研究与NFATc1结合的增强子，以了解哪些基因直接与NFAT结合并被NFAT激活，并找到帮助NFAT发挥作用的其他蛋白质。最后，我们还将了解NFATc1本身是如何在静脉内皮细胞中特异性地开启的。

The calcineurin-NFAT signaling pathway is involved in many important processes in our bodies. In particular, we know a lot about the crucial role this pathway plays in the immune system, where it switches on and off many key genes. However, less is known about what it does in other parts of the body. I am interested in understanding the control of blood vessel formation. This work focuses on endothelial cells, which form the inner lining of all vessels and are the first part of blood vessels to form. When NFAT signaling is inhibited, blood vessels do not form correctly. We recently examined mouse embryos that had lost NFAT signaling in the endothelium, and found that they have healthy arteries but defective veins. Arteries transport oxygen-rich blood to capillaries, while veins return the blood to the heart. Although vein endothelial cells are already known to be very different from their arterial counterparts, we do not understand how vein formation and growth is regulated. Based on the observations that veins were not formed correctly in NFAT mutant embryos, we looked at the binding pattern of the NFAT protein NFATc1. This revealed that NFATc1 binds directly to the enhancers (on-off switches) of many genes that are required for vein formation, suggesting that NFAT signaling may directly switch these on. In the project, we will analyse mouse and zebrafish embryos with defective NFAT signaling to establish why veins do not form properly. We will also investigate the enhancers that bind NFATc1 to both understand which genes are directly bound and activated by NFAT, and to find the other proteins which help NFAT function. Lastly, we will also find out how NFATc1 is itself able to switch on specifically in vein endothelial cells.