The Bedwell lab seeks to understand the mechanistic details of translation termination in eukaryotes, and to use that knowledge to develop therapeutic strategies for a range of genetic diseases caused by premature translation termination mutations (PTCs). In addition, other important cellular processes also intersect with the process of translation termination. For example, conserved cellular machineries also regulate the abundance of mRNAs based on the location of stop codons through the process of Nonsense-Mediated mRNA Decay (NMD). We are using a combination of genetics, biochemistry, and cell biology to better understand the molecular details of these processes.
Two diseases we are applying our findings to are cystic fibrosis (CF) and the lysosomal storage disease MPS I-H (Hurler syndrome). CF is caused by mutations in the CFTR gene. Roughly 10% of CF patients carry a premature stop mutation in the CFTR gene. We are working to identify drugs that suppress premature stop mutations in the CFTR gene in various experimental models, including cultured CF cells, transgenic and knock-in CF mice, and CF patients. We have also recently identified the amino acids inserted during the suppression of various stop codons in mammalian cells, and are using that informationto develop strategies to enhance the CFTR activity obtained by PTC suppression.
Similarly, 70% of Mucopolysaccharidosis Type I-H (MPS I-H) patients carry a premature stop mutation in the IDUAgene. We have shown that PTC suppression can alleviate the primary biochemical defect in primary cells and a knock-in Hurler mouse. In addition, we have shown that this approach can also moderate long-term progression of this disease in the brain, bone and heart. Ultimately, this therapeutic approach could be usedto treat a broad range of human genetic diseases caused by premature stop mutations.
Currently, our research is provided by the NIH, The University of Pennsylvania, and the Cystic Fibrosis Foundation.
