Regulation of VEGF splicing

血管内皮生长因子是血管生长（血管生成）的基本调节剂。它负责人类从胚胎到新生儿发育过程中所有组织的血管生长。它也是儿童发育成成人时组织生长的关键，在成人中，它是正常生理过程中组织重塑所必需的。G在运动后的肌肉生长中起作用)和许多疾病，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，细胞将编码血管最重要生长因子（VEGF）的基因编码的信息编辑在一起的方式产生了两个不同的蛋白质家族，分别是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，当VEGFxxx家族接管时，它被关闭。VEGFxxx家族刺激血管生长，而VEGFxxxb则阻止血管生长，我们最近发现了这个家族的许多新功能——它们保护细胞免受损伤，阻止疼痛的发展，维持肾功能和控制生育能力。现在很清楚，这种可选择的编辑（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发生切换。然而，在正常组织中，细胞是如何通过调节VEGF剪接来平衡这两个异构体家族的表达的，我们知之甚少。这一领域超出了医学研究慈善机构目前支持我们研究这些同种异构体是否可用于治疗癌症、心脏病、糖尿病、疼痛、肾衰竭和其他疾病的范围。本项目旨在确定调节VEGF mRNA剪接平衡的分子和细胞途径。它将确定控制这些剪接事件的一些分子，确定剪接因子识别的VEGF基因内的序列，并确定这种剪接平衡在活体动物中的改变方式和位置。它将使用一种新的、尖端的活体剪接报告技术来实现这一目标。这些是合成的DNA序列，根据形成的形式编码绿色或红色蛋白质。这些序列可用于在活细胞中实时跟踪剪接发生的方式。这是唯一的方法，剪接可以在一个活的单细胞内响应治疗，正常功能，或生长或动物的变化。这些新的序列是布里斯托尔实验室独有的，我们希望利用这一优势，在美国的竞争团体中产生来自英国基地的科学理解的进步。

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.