Cystic fibrosis (CF) is an inflammatory disease initiated by the loss of cystic fibrosis transmembrane conductance regulator (CFTR) function in epithelial cells. CFTR is a chloride channel whose activity is stimulated by PKA-mediated phosphorylation, and how a loss of this single chloride channel leads to the variety of symptoms associated with CF remains a mystery. The investigators have previously shown that nitric oxide (NO) production and the expression of the inducible form of nitric oxide synthase (NOS2) are reduced in CF airway epithelium. NO is known to regulate several transepithelial ion transport properties and act as a powerful anti-microbial agent, which may have biological significance in CF since CF is partially characterized by altered non-CFTR ion transport abnormalities and susceptibility to airway bacterial infections. Airway epithelium from other inflammatory airway diseases such as asthma have been shown to have increased expression of NOS2, but the mechanisms responsible for decreased NOS2 expression in the presence of such a robust inflammatory response seen in CF remain unclear. The investigators believe that alterations in the signal transducer and activator of transcription-1 (Stat 1) signaling pathway in CF epithelium are responsible for the puzzling lack of NOS2 expression. Their data indicate that increased levels of the protein inhibitor of activated Stat1 (PIAS1) bind the available activated phosphorylated-Stat1 (p-Stat1) in CF epithelial cells preventing Stat1 signaling which is necessary for NOS2 expression. This hypothesis also suggests that portions of interferon-y (IFN-y) dependent signaling would be lost in CF. This conclusion is supported by recently published data by Schwiebert et al. demonstrating reduced RANTES expression in response to IFN-y in CF epithelial cells compared to non-CF controls. Understanding the link between lost CFTR function and overexpression of PIASI will be a focus of this proposal, as will be determining the influence of IFN-y signaling on characteristics of CF-related disease. The aims of this proposal are: 1) to determine the influence of CFTR activity and function of PIAS1 expression and Stat1 pathway activity in epithelial cells; and 2) to determine the role of IFN-y/Stat1-dependent pathways and the effects of PIAS1 in regulating cellular responses with respect to known CF-related abnormalities. Learning how a loss of CFTR function leads to altered cell signaling processes and how these processes unfluence disease may increase our understanding of CF and lead to more precise therapeutic interventions.
NIH ExPorter
NIH ExPorter