Grant: Operating Grant

Hepatitis C virus (HCV) persists as a chronic infection in over 150 million people worldwide, and is a growing problem in Canada. New antivirals being developed will revolutionize HCV treatment in the developed world, but worldwide eradication of HCV will require antiviral agents that are more cost effective and do not induce virus resistance.With recent advances in cell biology, research scientists have realized that small RNAs (microRNAs), long overlooked as being biologically irrelevant, play important roles in cell regulation.A microRNA, miR-122, found specifically in liver cells, is normally involved in regulating the growth and metabolism of the liver, but in HCV infected cells binds directly to the HCV RNA genome and strongly enhances infection efficiency. that HCV relies on miR-122 is also its Achilles heel since methods to bind and inhibit miR-122 cripple the virus and interestingly do not to induce resistance. However, since the current methods used to inhibit miR-122 also inhibit the natural functions of miR-122, including its role in inhibiting cancer, there is concern associated with long-term miR-122 inhibition. Our underlying hypothesis is that: by identifying and blocking virus specific aspects of the mechanism by which miR-122 promotes virus infection we can inhibit HCV but not affect the normal role of miR-122. Unfortunately, we currently have an incomplete understanding of how miR-122 promotes HCV replication. The goal of my research program is to determine the mechanism of action of miR-122 in promoting HCV replication by identifying specific roles for host proteins, and regions of the viral genome involved. We will also test a method to target the miR-122 binding sites and induce destruction of HCV RNA by using an inexpensive nucleotide-based inhibitor. Our studies will lead to the development of a mechanistic model for the role of miR-122 in the HCV life cycle and identify novel targets for therapeutic intervention.