Investigation of the translational regulation of terminal oligo pyrimidine (TOP) containing mRNAs

我们身体的细胞是由一组叫做蛋白质的不同积木构成的。所有的蛋白质都可以通过翻译DNA遗传密码的特定片段来制造。一种叫做mRNA的中间物质被用于DNA和蛋白质之间；它将特定时间和地点所需的蛋白质遗传密码部分呈现给将其转化为蛋白质的机器。将mRNA翻译成蛋白质的“分子工厂”被称为核糖体，它由大约80种rna和蛋白质混合而成。没有核糖体，就不会产生蛋白质。当我们的细胞生长和分裂时，核糖体的每个组成部分的数量也必须翻倍，这样才能继续制造足够的蛋白质。核糖体组成部分比例不正确会导致细胞生长不足，或生长过度，因此不平衡会导致癌症等疾病。作为核糖体一部分的许多蛋白质在编码它们的mRNA中有一个独特的“标签”（称为TOP或末端寡聚嘧啶通道）。所有带有这个标签的mrna的翻译都与现有的核糖体紧密协调，以便它们的蛋白质以相同的时间和速度合成。虽然我们知道标签的存在，但我们并不完全了解它是如何被识别并用于控制新的核糖体制造的。我们的实验室已经做了初步的实验，发现了一组独特的蛋白质与标签结合。在这个应用程序中，我们建议精确地研究这些蛋白质如何与标签相互作用，以及彼此之间如何相互作用，以如此精确地协调核糖体的制造。我们的研究结果可以帮助我们了解当这种方法出错时癌症是如何发展的，并且从长远来看，可以提供治疗这种疾病的新方法。

Our bodies' cells are built from a diverse set of building blocks called proteins. All proteins can be made by translating specific pieces of the DNA genetic code. An intermediate material called mRNA is used between DNA and proteins; it presents the parts of the genetic code for proteins needed at a particular time and place to the machinery that translates it into proteins. The 'molecular factory' that translates mRNA into proteins is called the ribosome, made itself of a mixture of about 80 RNAs and proteins. Without ribosomes, no proteins could ever be made. When our cells grow and divide, the number of each of the component parts of ribosomes also has to double so that enough proteins can continue to be made. Incorrect proportions of component parts of the ribosome can cause cells not to grow enough, or to grow too much, and so imbalances can lead to diseases such as cancer. The many proteins whose job is to work as part the ribosome have a unique 'tag' (called a TOP or terminal oligopyrimidine tract) in the mRNA that encodes them. All mRNAs with this tag have their translation closely co-ordinated by existing ribosomes so that their proteins are made at the same time and rate. While we know about the existence of the tag, we do not fully understand how it is recognized and used to control new ribosome manufacture. Our lab has done initial experiments which reveal a unique suite of proteins that bind to the tag. In this application we propose to study exactly how these proteins interact with the tag, and with each other, to co-ordinate ribosome manufacture so accurately. Our results could help us to understand how cancers develop when this goes wrong, and, in the longer term, could provide new ways to tackle this disease.