Arrested lung development in preterm infants leads to bronchopulmonary dysplasia (BPD). Inflammation and NF-κB activation in the fetal lung inhibit airway morphogenesis and contribute to BPD. The mesenchymal growth factor FGF-10 is crucial for normal airway branching and is decreased in lungs of patients with BPD. I therefore hypothesized that when activated, NF-κB disrupts normal FGF-10 transcription. I discovered that FGF-10 is in fact downregulated by NF-κB activation, but in an indirect manner. Further analysis of the FGF-10 promoter revealed many sites consistent with regulation by Sp proteins. Experiments revealed that Sp1 and Sp3 also regulate FGF-10; Sp1 activates transcription, while Sp3 downregulates Sp1-mediated expression. I further discovered that Sp3 and the NF-κB dimer interact during FGF-10 suppression, suggesting that NF-κB recruits Sp3 to the FGF-10 promoter. This is a novel mechanism of gene regulation in the developing lung.
Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-08192013-174125 |
Date | 18 September 2013 |
Creators | Carver, Billy Joe |
Contributors | Lawrence Prince, Christopher Wright, Chin Chiang, Mark de Caestecker, Timothy Blackwell |
Publisher | VANDERBILT |
Source Sets | Vanderbilt University Theses |
Language | English |
Detected Language | English |
Type | text |
Format | application/pdf |
Source | http://etd.library.vanderbilt.edu/available/etd-08192013-174125/ |
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