Grant: Discovery Grants Program - Individual

This research program investigates new approaches for lowering the expression level of a particular gene using the natural RNA interference (RNAi) pathway. Since controlled gene expression levels are essential for proper biological function, the ability to silence or control the expression of genes is highly desirable. The RNAi pathway is a natural biological process that relies on short double-stranded RNAs to target gene specific messenger RNA. The potential of harnessing this natural pathway would have enormous impact on research and medicine worldwide, including Canada. However, the main pitfalls prohibiting the success of natural double-stranded RNAs as silencing agents are a) short-lifetime; b) toxicity and off-target effects; c) and poor cell-membrane permeability. The short-term goals in overcoming these obstacles are to chemically manipulate the siRNAs with stable non-natural groups. Our hypothesis is that by selectively placing stable functional groups within the backbone of siRNAs (in place of the labile negatively charged backbone) this will make them more resistant to degradation, will increase cell-membrane permeability, and potentially increase selectivity and specificity. Other short term goals include the biophysical characterization and a variety of cell-based functional assays. In short, this proposal will involve utilizing a combination of synthetic organic chemistry, bioorganic chemistry, biophysical chemistry, and biochemistry. The highly qualified personnel working on this research program will gain valuable training essential for success in their future careers. In conclusion, the long-term goal of our research program is to accurately predict the stability and specificity profile that chemically modified siRNAs have on its ability to illicit an RNAi response.