miRNA mechanism: genetics, quantitative tools and chemical genomics

The mechanism of miRNA action is still a matter of heated scientific debate. Furthermore, to date the analysis of miRNA-dependent gene regulation has been focused on a static model (fold reduction of protein or mRNA levels at steady-state), whereas miRNAs likely play important roles during temporal or spatial transitions. Indeed, modes of action that have been proposed for miRNAs include fine-tuning, thresholding or dampening of gene expression noise. We are using genetic and new, quantitative tools to investigate miRNA-dependent regulation of gene expression in vivo with single-cell, single-animal resolution. In addition, we have developed whole animal miRNA sensors that we use in high-throughput small molecule screens to discover small chemical tools that impinge on miRNA pathways. Small molecule leads from these screens are currently being developed in collaboration with a chemistry collaborator (Professor Shankar Balasubramanian). Although currently in the realm of chemical biology, some of the leads might move forward to a more translation effort including a drug discovery platform.