CANDIDATE: Steven M. Rowe, MD MSPH is committed to a career in academic pulmonology as a translational scientist focused on cystic fibrosis (CF) and other airways diseases. This proposal is intended to familiarize Dr. Rowe with the design and conduct of leading edge biomedical science in a closely mentored research environment. SPONSORS: Eric Sorscher, MD (Director, UAB CF Research Center) is a national leader in CF research and has extensive experience mentoring physician-scientists. JP Clancy, MD has worked daily with Dr. Rowe in related research projects and will provide instruction regarding the operation of a national multicenter CF clinical trial. George Howard, PhD will direct Dr. Rowe's advanced training in biostatistics. ENVIRONMENT: UAB is well suited to provide translational research training, including state-of-the-art research facilities and excellent career development resources. RESEARCH: CF caused by premature stop mutations results in the production of little or no functional cystic fibrosis transmembrane conductance regulator (CFTR). Certain small molecules have the capacity to reduce the fidelity of nonsense allele recognition, leading to translational readthrough of otherwise truncated CFTR and synthesis of full-length, active protein. This strategy has been successfully employed to correct CFTR function in CF subjects in vivo. A better understanding of mechanisms of action and investigation of more potent agents is required to advance this new treatment strategy. We will study the effects of stop mutation susceptibility to translational readthrough, and evaluate the importance of mRNA stability in this process. PTC124, a new compound that confers very potent stop suppression, will be evaluated in vitro and in a clinical trial. Successful completion of this project will define the potential role of nonsense codon suppression as a future CF therapy. LAY STATEMENT: Correcting premature stop mutations could improve or cure patients with CF and other genetic diseases caused by stop mutations. We propose to study this approach in the laboratory and in a clinical trial using a new, very active compound named PTC124. Results will help determine whether this treatment strategy can be used to treat individuals with CF and other inherited diseases.
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