Functional significance of VEGF regulation by SRPK1

人类的基因非常少--总共大约22000个。尽管如此，我们可以制造成千上万种不同的基因产物--使身体工作的蛋白质。每个基因可以通过使用基因的不同部分产生多种蛋白质-这一过程称为选择性剪接。在这个过程中，由基因DNA编码的不同序列粘在一起，发出不同的信息来制造蛋白质。这类似于将电影中的不同场景拼接在一起，形成不同的故事--插入不同的结局可以将故事从悲剧变成浪漫。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作出反应-包括癌症、糖尿病、失明和肾脏疾病。血管需要两种类型的生长因子VEGF之间的平衡才能正常工作。这两种类型是通过这种选择性剪接过程制成的。一种类型的VEGF使新血管渗漏，生长成新组织，并导致最常见形式的失明（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。另一种类型是通过在蛋白质的不同末端拼接而成的，它可以防止新血管的生长，并保护肾脏免受糖尿病、失明和癌症的影响。细胞用来决定产生这两种形式中哪一种的编辑过程有许多步骤，其中一些提供特异性，以允许产生不同形式的分子。我们以前发现这些步骤是由两种蛋白质SRPK 1和SRSF 1执行的。该项目将发现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病。我们将通过使用新发现的药物和已开发用于研究这些分子的遗传小鼠模型，并通过生成新的小鼠模型来帮助我们了解SRPK 1的工作原理。

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.