My research goal is to better understand molecular mechanisms that control eukaryotic gene expression at the RNA level. Within this framework, I am exploring three issues:
- Noncoding RNAs and their roles in gene expression
- Nuclear pre-mRNA splicing, and finally
- Specific RNA:RNA and RNA:Protein interactions
The current emphasis of the lab is on miRNA-mediated regulation of human androgen receptor expression. Androgen receptor is a key 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 particularly interesting idea that I would like to investigate further is the critical level of Androgen receptor influences the transition from the hormone-dependent to hormone refractory stage of prostate cancer. Using computational biology tools I have identified a number of miRNAs that have the potential to 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 in the progression of prostate cancer. Using lentiviral expression systems we are overexpressing a number of miRNAs to understand how androgen receptor expression is controlled by these miRNAs in a variety of prostatic carcinoma cells.
The research in my laboratory is also aimed at understanding the 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 further define their role in the splicing of minor class introns. We are also studying specific RNA-RNA base-pairing interaction involved in the splicing of the minor class intron using biochemical and in vivo genetic approaches. These studies will help us to understand how multiple sequentially interacting snRNAs facilitate the removal of introns from the precursor mRNA of genes.