Regulation of VEGF splicing

血管内皮生长因子是血管生长(血管生成)的基本调节因子。它负责人类发育过程中从胚胎到新生儿的所有组织中的血管生长。在儿童成长为成年人的过程中，它也是组织生长的关键，对于成年人来说，它在正常的生理过程中是必要的，在组织重构过程中(例如，在肌肉对运动的反应中)，以及在许多疾病中，包括癌症、糖尿病和心脏病。在过去的三年里，我们的研究小组发现，细胞编辑由编码最重要的血管生长因子(称为血管内皮生长因子)的基因编码的信息的方式，导致了两个不同的蛋白质家族，分别称为VEGFxxx和VEGFxxxb。VEGFxxxb家族在正常人体组织中广泛表达，但在血管生成过程中被关闭，当VEGFxxx家族接管时。VEGFxxx家族刺激血管生长，而VEGFxxxb阻止血管生长，我们最近发现了该家族的许多新功能-它们保护细胞免受损伤，阻止疼痛发展，维持肾脏功能，并控制生育。现在很清楚，这种选择性编辑(剪接)是由细胞控制的，并且似乎在血管生成和其他细胞应激过程中切换。然而，关于细胞如何通过调节正常组织中血管内皮生长因子的剪接来平衡这两个亚型家族的表达，人们知之甚少。这一领域超出了目前支持我们的工作的医学研究慈善机构的范围，目的是了解这些异构体是否可以用于治疗癌症、心脏病、糖尿病、疼痛、肾功能衰竭和其他疾病。该项目旨在确定调节血管内皮生长因子mRNA剪接平衡的分子和细胞途径。它将识别控制这些剪接事件的一些分子，确定剪接因子识别的血管内皮生长因子基因内的序列，并确定这种剪接平衡在活体动物中如何以及在哪里发生变化。它将使用一种新的、尖端的体内剪接记者技术来做到这一点。这些是合成的DNA序列，根据形成的形式对绿色或红色蛋白质进行编码。这些序列可以用来在活细胞中实时跟踪剪接发生的方式。这是在活的单个细胞内进行剪接的唯一方法，以响应治疗、正常功能或动物的生长或变化。这些新的序列是布里斯托尔实验室独有的，我们希望利用这种相对于美国竞争小组的优势，从英国基地产生科学理解方面的进步。

Vascular Endothelial Growth Factor is fundamental regulator of blood vessel growth (angiogenesis). It is responsible for blood vessel growth in all tissues in human development from the embryo to the newborn child. It is also key to growth of tissues as children develop into adults, and in adults it is necessary in normal physiology during tissue remodelling (e..g in muscle growth in response to exercise) and in many diseases including cancer, diabetes and heart disease . Over the last three years, our research group has discovered that the way that cells edit together the message encoded by the gene that codes for the most important growth factor for blood vessels (called VEGF) results in two different families of proteins called VEGFxxx and VEGFxxxb. The VEGFxxxb family is widely expressed in normal human tissues, but switched off during angiogenesis, when the VEGFxxx family take over. The VEGFxxx family stimulates blood vessel growth, whereas the VEGFxxxb stops vessels growing, and we have recently identified many new functions of this family - they protects cells from injury, stop development of pain, maintain kidney function, and control fertility. It is now clear that this alternative editing (splicing) is controlled by cells, and appears to switch during angiogenesis and other cell stresses. However, little is known about how cells balance expression of the two families of isoforms by regulating splicing of VEGF in normal tissues. This area is beyond the scope of the medical research charities currently supporting our work to find out whether these isoforms can be used to treat cancers, heart disease, diabetes, pain, renal failure and other conditions. This project aims to determine the molecular and cellular pathways that regulate the balance of splicing of the VEGF mRNA. It will identify some of the molecules that control these splicing events, determine the sequences within the VEGF gene that are recognised by splicing factors, and identify how and where this splicing balance alters in live animals. It will do so using a new, cutting edge technology of in vivo splice reporters. These are synthetic DNA sequences that code for green or red proteins depending on which forms are made. These sequences can be used to follow in real time in live cells which way splicing is happening. This is the only way that splicing can be followed within a live single cell in response to treatments, to normal function, or growth or changes in animals. These new sequences are unique to the laboratory in Bristol, and we wish to exploit this advantage over competing groups in the USA to generate advances in scientific understanding from a UK base.