In cystic fibrosis (CF), loss of the CFTR CI- channel disrupts airway epithelial electrolyte transport, thereby contributing directly to the disease pathogenesis. Two processes control the activity of the CFTR CI-channel: phosphorylation of its R domain and ATP interactions with its nucleotide-binding domains (NBDs). This project focuses on these two regulatory mechanisms. 1. Regulation of CFTR CI- channel activity by phosphorylation motifs in the R domain. Our recent structural and functional studies suggest that R domain phosphorylation motifs and their flanking residues are central to regulation. We will probe CFTR function with phosphorylated and unphosphorylated R domain peptides comprising these motifs. This novel strategy will reveal mechanisms by which the R domain regulates CFTR. 2. Control of CFTR CI- channels by adenylate kinase activity. For a long time we have known that the CFTR can hydrolyze ATP (ATP++ADP+Pi). Our preliminary data suggest that in addition to its ATPase activity, CFTR has adenylate kinase activity (ATP+AMP'2ADP). We will test how this novel enzymatic activity controls channel activity and identify responsible mechanisms. By using powerful new approaches and by testing novel hypotheses, the results of this work will give us an unprecedented look at how CFTR works. As we focus on very specific structural elements and enzymatic mechanisms, our data will help explain earlier results and will yield exciting new insight into the relationship between CFTR structure and function. The results will have substantial implications for the function of other medically important ABC transporters and for the development of new treatments for CF.
| Bartlett, Jennifer A; Meyerholz, David K; Wohlford-Lenane, Christine L et al. (2015) Increased susceptibility to otitis media in a Splunc1-deficient mouse model. Dis Model Mech 8:501-8 |
| Bartlett, Jennifer A; Albertolle, Matthew E; Wohlford-Lenane, Christine et al. (2013) Protein composition of bronchoalveolar lavage fluid and airway surface liquid from newborn pigs. Am J Physiol Lung Cell Mol Physiol 305:L256-66 |
| Reed, Matthew D; McCombie, Barbara E; Sivillo, Aimee E et al. (2012) Safety assessment of nebulized xylitol in beagle dogs. Inhal Toxicol 24:365-72 |
| Dong, Qian; Ostedgaard, Lynda S; Rogers, Christopher et al. (2012) Human-mouse cystic fibrosis transmembrane conductance regulator (CFTR) chimeras identify regions that partially rescue CFTR-?F508 processing and alter its gating defect. Proc Natl Acad Sci U S A 109:917-22 |
| Pezzulo, Alejandro A; Starner, Timothy D; Scheetz, Todd E et al. (2011) The air-liquid interface and use of primary cell cultures are important to recapitulate the transcriptional profile of in vivo airway epithelia. Am J Physiol Lung Cell Mol Physiol 300:L25-31 |
| Schmidt, Nathan W; Mishra, Abhijit; Lai, Ghee Hwee et al. (2011) Criterion for amino acid composition of defensins and antimicrobial peptides based on geometry of membrane destabilization. J Am Chem Soc 133:6720-7 |
| Bartlett, Jennifer A; Bartlett, Jennifer; Gakhar, Lokesh et al. (2011) PLUNC: a multifunctional surfactant of the airways. Biochem Soc Trans 39:1012-6 |
| Itani, Omar A; Chen, Jeng-Haur; Karp, Philip H et al. (2011) Human cystic fibrosis airway epithelia have reduced Cl- conductance but not increased Na+ conductance. Proc Natl Acad Sci U S A 108:10260-5 |
| Fischer, Anthony J; Lennemann, Nicholas J; Krishnamurthy, Sateesh et al. (2011) Enhancement of respiratory mucosal antiviral defenses by the oxidation of iodide. Am J Respir Cell Mol Biol 45:874-81 |
| Gakhar, Lokesh; Bartlett, Jennifer A; Penterman, Jon et al. (2010) PLUNC is a novel airway surfactant protein with anti-biofilm activity. PLoS One 5:e9098 |
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