Functional significance of VEGF regulation by SRPK1

人类的基因非常少，总共大约有22000个。尽管如此，我们仍然可以制造出成千上万种不同的基因产物——使身体正常工作的蛋白质。每个基因可以利用基因的不同部分产生多种蛋白质，这一过程被称为选择性剪接。在这个过程中，来自基因的DNA编码的不同序列被粘在一起，发出不同的信息来制造蛋白质。这就好比把电影中不同的场景拼接成不同的故事——插入一个不同的结局可以把一个故事从悲剧变成浪漫。在人类发育、正常功能和疾病中，最重要的过程之一是血管如何生长和对损伤做出反应——包括癌症、糖尿病、失明和肾脏疾病。血管需要两种生长因子VEGF之间的平衡才能正常工作。这两种类型是由这种选择性剪接工艺制成的。一种类型的VEGF使新血管渗漏，生长成新的组织，并导致最常见的失明形式（湿性年龄相关性黄斑变性和糖尿病视网膜病变），肾衰竭和癌症。另一种类型是通过剪接蛋白质的不同末端而产生的，它可以防止新的血管生长，保护肾脏免受糖尿病、失明和动物癌症的损害。细胞用来决定生成这两种形式中的哪一种的编辑过程有许多步骤，其中一些步骤提供了特异性，以允许生成不同形式的分子。我们之前发现这些步骤是由两个蛋白SRPK1和SRSF1完成的。这个项目将找出这些分子是如何工作的，以及抑制它们是否可以预防动物失明和遗传性肾脏疾病。我们将使用新发现的药物和遗传小鼠模型来研究这些分子，并通过生成一个新的小鼠模型来帮助我们了解SRPK1是如何工作的。

Human beings have remarkably few genes - about 22000 in total. Despite this we can make hundreds of thousands of different gene products - the proteins that make the body work. Each gene can generate multiple proteins by use of different parts of the gene - a process called alternative splicing. In this process different sequences coded by the DNA from the gene are stuck together to give a different message to make proteins. This is analogous to splicing together different scenes from a film to make different stories - cutting in a different ending can change a story from a tragedy to a romance. One of the most important processes in human development, normal function and disease, is how blood vessels grow and respond to injury - including in cancer, diabetes, blindness and kidney disease. Blood vessels require a balance between two types of the growth factor VEGF to work properly. These two types are made by this alternative splicing process. One type of VEGF makes new blood vessels that are leaky, grow into new tissue, and contribute to the most common forms of blindness (wet age related macular degeneration and diabetic retinopathy), kidney failure and cancer. The other type, made by splicing in a different ending to the protein, prevents new vessel growth and protects kidneys from failure in diabetes, and blindness and cancer in animals. The editing process that the cell uses to decide which of these two forms are generated has a number of steps in it, some of which provide specificity, to allow different forms of molecules to be made. We previously found that these steps are carried out by two proteins, SRPK1 and SRSF1. This project will find out how these molecules work, and whether inhibiting them can prevent blindness and hereditary kidney disease in animals. We will do this by using newly discovered drugs and genetic mouse models that have been developed to study these molecules, and by generating a new mouse model that will help us understand how SRPK1 works.