This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Mutations in the CFTR gene are responsible for cystic fibrosis (CF). The most common mutation, F508 inhibits CFTR biogenesis and leads to the absence of CFTR at the plasma membrane. When F508-CFTR is allowed to traffic to the apical plasma membrane, it is partially functional as a Cl- channel. Thus, restoration of the apical membrane expression of F508-CFTR is a potential therapeutic approach for CF, currently under investigation by several research laboratories. However, the apical membrane half-life of F508-CFTR is reduced and the mechanism remains unknown. Thus, our central hypothesis is that the short apical membrane half-life of F508-CFTR results from altered regulation of F508-CFTR trafficking at the apical membrane.
Our specific aims are:1. To test the hypothesis that the short apical membrane half-life of F508-CFTR results from either accelerated endocytosis or attenuated endocytic recycling or both.2. To elucidate the adaptor protein complexes that facilitate trafficking of wt-CFTR and F508-CFTR at the apical membrane.3. To identify the mechanisms by which the adaptor protein complexes regulate trafficking of wt-CFTR and F508-CFTR at the apical membrane.
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