Mechanistic determination of how microRNAs control gene-expression

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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.