My research goal is to understand better molecular mechanisms that control eukaryotic gene expression at the RNA level. Within this framework, I am exploring three issues: (1) noncoding RNAs and their roles in gene expression, (2) nuclear pre-mRNA splicing, (3) specific RNA: RNA and RNA: Protein interactions, and finally (3) post-transcriptional control and cancer therapeutics. The current emphasis of the lab is on miRNA-mediated regulation of human androgen receptor expression and post-transcriptional control of steroid biosynthesis. Androgen receptor is a critical modulator that has been implicated in hormonal dependent and independent stages of prostate cancer. Based on computational predictions and phylogenetic analysis, I have proposed a miRNA-mediated model of Androgen Receptor regulation. One fascinating idea that I would like to investigate further is the critical level of the Androgen receptor that influences the transition from the hormone-dependent to the hormone-refractory stage of prostate cancer. Using computational biology tools, we have identified many miRNAs that can potentially interact with the 3' untranslated region of the receptor mRNA. This observation gives rise to the hypothesis that androgen receptor expression is tightly regulated by combinatorial control of miRNAs, and deregulation of these miRNAs may contribute to prostate cancer progression. We have identified several rate-limiting critical enzymes in the steroid biosynthesis pathways that have the potential for targeted cancer therapy. We are focusing on the molecular mechanisms of these enzymes using a variety of cutting-edge molecular tools.
The research in my laboratory also aims to understand nuclear pre-mRNA splicing by using in vitro and in vivo methods. We are currently studying the structure-function of several snRNAs of the minor spliceosome, including U11, U12, U4atac, and U6atac. Recently we have identified a small RNA element in the U6atac snRNA that functions in the 'guiding' of the specific spliceosomal complexes to the minor class splice sites. We are now pursuing the identification of proteins that may interact with these U6atac snRNA sub-structures to define their role in the minor spliceosome further. We are also studying specific RNA-RNA base-pairing interactions involved in splicing the minor class intron using biochemical and in vivo genetic approaches. These studies will help us understand how multiple sequentially interacting snRNAs facilitate the removal of introns from the precursor mRNA of genes.