Mechanistic determination of how microRNAs control gene-expression

最近，一种全新的控制基因表达的方法被发现。这是在发现了一类新的基因后发现的，与大多数基因不同，这类基因不产生蛋白质，而是被加工成称为microRNA的短RNA分子。人类基因组中大约有1000种不同的microRNA，它们都有不同的作用。它们通过与蛋白质编码基因的信使RNA结合并抑制信使RNA内编码的蛋白质的产生来起作用。这1000个小RNA分子中的每一个被认为与大约200个蛋白质编码基因相互作用并调节，从而增加了人类基因组调节的复杂性。现在已经很清楚，miRNA调控的功能障碍与几乎所有的人类疾病有关，包括：癌症、糖尿病和病毒感染。2002年，《科学》杂志将miRNA称为年度突破，这些小RNA分子被称为“细胞的暗物质”。microRNA直到2001年才被发现，令人惊讶的是，在这短短的时间内，基于microRNA的药物已经在许多人类疾病的临床试验中，证明了该领域研究的有用性。然而，尽管在这一领域取得了迅速的进展，这些小RNA分子如何发挥其对蛋白质生产的影响目前还不清楚和有争议的。由于操纵这些小RNA分子是治疗许多人类疾病的现实方法，因此了解这些治疗剂如何工作对于它们的开发和安全使用至关重要。该提案旨在确定这些小RNA分子控制人体内蛋白质产生的机制，并通过提供可由世界各地许多实验室探索的可测试模型来解决该领域的争议。

Recently, a completely new way of controlling gene expression has been discovered. This has come to light after the identification of a new class of genes, which unlike most genes do not produce proteins, but instead are processed into short RNA molecules called microRNAs. There are around 1000 different microRNAs within the human genome, all of which have different effects. They work by binding to the messenger RNA of protein encoding genes and inhibiting production of the protein encoded within the messenger RNA. Each of these 1000 small RNA molecules is believed to interact with and regulate around 200 protein encoding genes, thus adding to the complexity of the regulation of the human genome. Already it has become clear that malfunction of miRNA regulation is associated with virtually all human disease, including: cancer, diabetes, and viral infections. In 2002 Science magazine called miRNA the breakthrough of the year, and these small RNA molecules have been termed the "Dark Matter of the cell". MicroRNAs were only discovered in 2001 and, amazingly, already within this short period, microRNA-based drugs are in clinical trials for a number of human diseases demonstrating the usefulness of the research within this field. However, despite the rapid advances within this field, how these small RNA molecules exert their effects on protein production is currently unclear and controversial. As manipulation of these small RNA molecules is a realistic approach for the treatment of a number of human diseases, understanding how these therapeutic agents work will be critical for their development and safe use. This proposal aims to determine the mechanism by which these small RNA molecules control the production of proteins within the human body and to resolve the controversy within the field by supplying testable models which can be probed by many laboratories around the world.