Understanding the pharmacology of SLC28 group of concentrative nucleoside transporters

 

Understanding the pharmacology of SLC28 group of concentrative nucleoside transporters
The concentrative nucleoside transporter (CNTs) proteins encoded by SLC28 genes play crucial biological roles by transporting nucleosides across the cell and cellular organelle membranes. They also transport nucleoside analogs used for the treatment of cancer and viral infections. Their high-affinity, exquisite substrate selectivity and unidirectionality (allows cell influx only) suggest their potential to significantly influence nucleoside disposition and cellular homeostasis, yet, there are no definitive evidence linking CNTs to nucleoside action. Using the sandwich-cultured human hepatocyte model, the mouse intestinal perfusion model and the mouse orthotopic tumor xenograft model, we have obtained vital clues about the involvement of CNTs in nucleoside-directed cellular signaling and synthetic nucleoside analog drug disposition. Nonetheless, further understanding is stalled due to lack of suitable in vivo models that can comprehensively evaluate CNTs in the context of whole-body or in relation to other nucleoside transporter/metabolism genes. In this project, we create and characterize all three CNT (CNT1, CNT2, CNT3) knockout mouse models in order to understand the biological and pharmacological roles of these proteins.