Harvard University, Ph.D. Biochem. & Mol. Biol.,
1) Molecular mechanisms that coordinate the control of cell proliferation and differentiation during normal development
We use the Drosophila developing eye as a model system to elucidate mechanisms by which developmental mechanisms coordinate cell proliferation and differentiation. In third instar eye discs, photoreceptor differentiation initiates in the morphogenetic furrow (MF). Cells anterior to the MF are asynchronously proliferating, which become cell cycle arrest in G1 in the MF. posterior to the MF, the differentiating photoreceptors are arrested in G1 while the remaining cells undergo a synchronous round of cell cycle called second mitotic wave (SMW). The Notch and EGFR developmental signaling pathways and the bHLH proteins Atonal are implicated in the coordinated control of these processes. Therefore we are dissecting the regulation of Ato expression and investigating the molecular mechanisms by which cell proliferation and differentiation are coordinately regulated.
2) Novel approaches to target the loss of Rb tumor suppressors in cancers
Rb is a tumor suppressor that is often lost in cancers. In a genetic screen for genes that can modulate the consequences of Rb loss, we found that mutation of gig, the Drosophila TSC2 homolog, show synergistically increased cell death with loss of Rb. Interestingly, knockdown of TSC2 in human cancer cells blocks cancer cell growth and induced cell death dependent on the Rb status, suggesting that TSC2 can potentially be used to specifically target Rb mutant cancers.
Current research in the lab include further characterization of the mechanisms of synergistic cell death induction, identification of genes/pathways/chemical inhibitors that can enhance the specific cell death induction by TSC2 knockdown, developing assays to screen for small molecule inhibitors of TSC2 function, and carry out additional genetic screen to identify additional potential targets.