Our lab is focused on the development of targeted delivery of RNAi and ASO therapeutics. We pioneered the synthesis of bioreversible, charge neutral phosphotriester-backbone modifications, called short interfering RiboNucleic Neutrals (siRNNs). We are currently synthesizing and screening next generation non-toxic endosomal escape domains. Using differential conjugation approaches, we combine these different chemistries together with site specific targeting domains (carbohydrates, small molecules, and mAbs) to generate Targeted-RNA Conjugates or TRCs with the ultimate goal of treating cancer, infectious diseases and CNS diseases.
We also have a long-standing interest in understanding the regulation of early to late G1 cell cycle progression in cancer. We have shown that cyclin D:Cdk4 activates the RB tumor suppressor in early G1 phase by generating 14 individual mono-phosphorylated RB isoforms that each preferentially bind specific and overlapping targets. Activation of cyclin E:Cdk2 at the early to late G1 Restriction Point transition performs the initial RB inactivation by hyper-phosphorylation (14x phosphates per RB). Our goal is to understand the regulatory interplay of activating and inactivating cyclin:Cdk complexes on RB and how these are deregulated in cancer.