In cystic fibrosis, genetic mutations cause a loss of function in CFTR, a channel protein that regulates the flow of salt and water across epithelial membranes. Dr. Madden's research program explores the stereochemical determinants of protein-protein interactions that control the post-endocytic trafficking of CFTR within epithelial cells. At a fundamental level, our challenge is to understand the specificity of these "molecular handshakes" -- how the correct connections are made in a crowded cellular environment. At the same time, these interactions influence CFTR abundance and function. As a result, they represent pharmaceutical targets that could enhance the efficacy of existing and future therapies for patients with CF. Current research uses peptide-array and high-throughput screening approaches to identify selective inhibitors, and structural and cellular assays to characterize them.
Within DartCF, these studies form part a broad strategy to explore metabolic and signaling interactions within and among epithelial, immune, and microbial cells. These networks govern the balance between eubiosis and dysbiosis at the epithelial interface. DartCF focuses in particular on developing expertise in gut epithelial function, models of epithelial-microbe interactions, clinical and translational resources, and integrative analytical approaches. In parallel, it partners with other CF research programs at Dartmouth, including the CF Clinic, the CF Foundation Therapeutics Development Network, and the CF Lung Biology Center, which is separately supported by a CFF Research Development Program award.