A major objective of research in Dr. Bedwell’s lab is to understand the mechanistic details of translation termination in eukaryotes. Besides the release factors eRF1 and eRF3, many other cellular components influence the process of translation termination. Cellular machineries also regulate the abundance of mRNAs that carry a premature stop codon via a mechanism called Nonsense-Mediated mRNA Decay (NMD). He is using a combination of genetics, biochemistry, and cell biology in a yeast experimental system to better understand the molecular details of how these processes are carried out.
Dr. Bedwell is also investigating whether pharmacological agents can be used to suppress nonsense mutations that cause genetic diseases. First, he is exploring whether this novel therapeutic approach can benefit patients with cystic fibrosis (CF). CF is caused by mutations in the CFTR gene (which corresponds to the mouse Cftr gene). Dr. Bedwell and his laboratory have published several papers demonstrating that drugs can suppress nonsense mutations in the CFTR gene in various CF experimental systems, including cultured CF cell lines and a CF mouse expressing a human CFTR-G542X transgene. Most recently, he has constructed a new Cftr-G542X knock-in mouse model to explore this approach in a more physiologically relevant context.
Dr. Bedwell is also investigating whether this therapeutic approach can benefit patients with the lysosomal storage disease mucopolysaccharidosis type I-H (MPS I-H, or Hurler syndrome). MPS I-H is caused by mutations in the human IDUA gene (which corresponds to the mouse Idua gene). He has constructed a Idua-W392X knock-in mouse and have preliminary evidence that nonsense suppression can partially alleviate the primary biochemical defect that causes this devastating genetic disease.
Finally, the availability of the knock-in mouse models for CF and MPS I-H will allow him to explore whether the suppression of Nonsense-Mediated mRNA Decay (NMD) can further enhance the therapeutic effect provided by nonsense suppression agents. It is hoped that either nonsense suppression alone or in combination with NMD suppression will ultimately provide a therapeutic benefit for a broad range of human genetic diseases caused by nonsense mutations.