Pseudomonas aeruginosa infection is the major cause of morbidity and mortality in cystic fibrosis. The organism persists in airways in large part through its ability to generate energy under the oxygen-limited conditions that define the dehydrated mucus in diseased lungs. This small-grant project will advance knowledge of transcription regulatory mechanisms that control energy metabolism. The Anr and Dnr proteins, members of the Crp-Fnr superfamily of transcription activators, are thought to differentially regulate expression of genes whose products are required for microaerobic or anaerobic respiration. The mechanism for this differential regulation is unclear. One hypothesis is that distinct specificity determinants for Anr and Dnr binding serve to direct each regulator to the appropriate operons. An alternative hypothesis is that Anr and Dnr have similar binding specificity determinants, but that these regulators function under different physiological conditions. I propose to distinguish between these two hypotheses by comparing expression from two representative transcription control regions. In previous studies by others, the arcD operon encoding arginine fermentation enzymes has been suggested to be regulated exclusively by Anr, whereas the nosR operon encoding nitrous oxide reductase has been suggested to be regulated exclusively by Dnr. Experiments will monitor arcD- and nosR-directed transcription under different growth conditions, in anr and dnr null mutants, and in strains in which anr and dnr are expressed constitutively. Results from these tests will provide the basis for further analysis of Anr and Dnr control of microaerobic and anaerobic respiration. If the first hypothesis is correct, the determinants for differential binding specificity will be identified. If the second hypothesis is correct, specific roles for Anr- and Dnr- regulated gene expression will be examined further in order to document specific responses to physiological parameters such as oxygen limitation and nitric oxide.
Pseudomonas aeruginosa infection is the major cause of morbidity and mortality in cystic fibrosis. The organism persists in airways in large part through its ability to generate energy under the oxygen-limited conditions that define the dehydrated mucus in diseased lungs. This small-grant project will advance knowledge of transcription regulatory mechanisms that control energy metabolism.
| Pisetsky, David S; Grammer, Amrie C; Ning, Tony C et al. (2011) Are autoantibodies the targets of B-cell-directed therapy? Nat Rev Rheumatol 7:551-6 |
