Research Project
7221889
DESCRIPTION (provided by applicant): Double-strand RNA (dsRNA) mediated post-transcriptional gene silencing (PTGS), also known as RNAi, is a phenomenon in which genes are silenced in a sequence dependent manner at the level of mRNA degradation. PTGS, a well-documented phenomenon in many plant and animal species, has been demonstrated to also occur in mammalian systems. Preliminary data in our lab also suggests that PTGS can occur, in vivo, in adult mice. Induction of PTGS in mammalian systems however, appears to be more difficult to achieve relative to its induction in invertebrates. Part of the difficulty lies in avoiding the interferon response pathway which is also induced by dsRNA. Clearly, much more work is needed to define the parameters and conditions needed for efficient and consistent induction of PTGS in mammals. Our objectives are to define the parameters required for optimal induction of PTGS in cell culture and in vivo, in adult mouse models. The development of PTGS-based therapeutics is potentially a viable strategy for down-regulating gene products involved in disease pathways. Our objective is to evaluate this strategy for one disease model, Hepatitis B virus (HBV) infection. Chronic HBV infection represents an ideal target for potential therapeutic strategies since RNA is an intermediate in both HBV replication and expression. Furthermore, a PTGS-based therapeutic, unlike current nucleoside analogue therapies, is predicted to not only decrease viral titers but to also effect decreases in antigen load. In addition, as no significant homology exists between HBV sequences and host sequences, elicited silencing is predicted to be exclusive for HBV.
