Cystic fibrosis (CF), one of the most common genetic disorders in the Caucasian population. Mutations in the gene that encodes for the CFTR are the genetic basis for CF. CFTR is a multifunctional protein that acts as a cAMP-activated CI- channel and an ion conductance regulator. CFTR is a member of the ATP-Binding Cassette Transporter superfamily of transmembrane proteins. This family is characterized by a highly conserved ATP binding cassette known as a nucleotide binding fold (NBF). Many of the disease-producing mutations reside within the NBF domains of CFTR. The first nucleotide binding domain(NBF1) has been identified as an essential region for CFTR's interactions with other ion channels. Our general hypothesis is that in CF, there is an inability of CFTR to function as an ion conductance regulator, as well as a cAMP-stimulated CI- channel. We postulate that it is the combination of these functions that leads to ion transport abnormalities and alterations in airway surface fluid that eventually result in lung disease. Therefore, understanding the mechanisms that underlie CFTR's ability to act as a conductance regulator may be extremely important in our basic understanding of the pathophysiology of CF. The proposed studies will examine CFTR's interactions with ion channels concentrating on NBF1, a region implicated in both CFTR's ability to function as a conductance regulator and chloride channel. Specifically, DF508-CFTR, the most common mutation, will be examined. Electrophysiological, biochemical and molecular techniques will be used to determine the effects of the DF508 mutation on CFTR's ability to function as a conductance regulator. The ultimate goal of this project is to apply the insights gained from these basic science studies of CFTR function to improve the clinical management of cystic fibrosis patients.
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