The long-term goals of this component seek to 1) elucidate the hierarchy of transcriptional controls that determine the commitment of progenitor cells that produce the differentiated cells of the developing and mature respiratory epithelium and 2) utilize transcriptional control elements governing lung epithelial cell gene expression to determine the pathogenesis of acute and chronic lung disorders such as respiratory distress syndrome, pulmonary fibrosis, bronchopulmonary dysplasia and other disorders of surfactant homeostasis. Our analysis of the transcriptional controls of surfactant proteins A, B, C and CC10 provided critical insight into the role of thyroid transcription factor 1 (TTF-1), a 38 kilosdalton homeodomain, containing protein of the NK-2 family, and the HNF-3 family of nuclear transcription proteins in lung-specific gene expression. We hypothesize that these proteins bind to and activate promoter elements that control the temporal, spatial and humoral influences on lung epithelial cell gene expression. The present application will now determine the role of TTF-1 and HNF-3alpha in lung development, differentiation and gene expression using gene ablation and gene addition experiments in vitro and in vivo. The mechanisms controlling TTF-1 gene expression in the developing lung epithelium will be discerned. Downstream targets activated by TTF-1 will be identified by differential display to determine their roles in gene expression and surfactant homeostasis in developing and mature lung.
| Sadayappan, Sakthivel; Finley, Natosha; Howarth, Jack W et al. (2008) Role of the acidic N'region of cardiac troponin I in regulating myocardial function. FASEB J 22:1246-57 |
| Pattison, James Scott; Waggoner, Jason R; James, Jeanne et al. (2008) Phospholamban overexpression in transgenic rabbits. Transgenic Res 17:157-70 |
| Kalinichenko, Vladimir V; Gusarova, Galina A; Kim, Il-Man et al. (2004) Foxf1 haploinsufficiency reduces Notch-2 signaling during mouse lung development. Am J Physiol Lung Cell Mol Physiol 286:L521-30 |
| Small, Kersten M; McGraw, Dennis W; Liggett, Stephen B (2003) Pharmacology and physiology of human adrenergic receptor polymorphisms. Annu Rev Pharmacol Toxicol 43:381-411 |
| Sanbe, Atsushi; Gulick, James; Hanks, Mark C et al. (2003) Reengineering inducible cardiac-specific transgenesis with an attenuated myosin heavy chain promoter. Circ Res 92:609-16 |
| Liggett, Stephen B (2003) Polymorphisms of adrenergic receptors: variations on a theme. Assay Drug Dev Technol 1:317-26 |
| Golovina, Vera A; Song, Hong; James, Paul F et al. (2003) Na+ pump alpha 2-subunit expression modulates Ca2+ signaling. Am J Physiol Cell Physiol 284:C475-86 |
| Lim, Lorena; Kalinichenko, Vladimir V; Whitsett, Jeffrey A et al. (2002) Fusion of lung lobes and vessels in mouse embryos heterozygous for the forkhead box f1 targeted allele. Am J Physiol Lung Cell Mol Physiol 282:L1012-22 |
| Pietri, Laurence; Bloch-Faure, May; Belair, Marie-France et al. (2002) Altered renin synthesis and secretion in the kidneys of heterozygous mice with a null mutation in the TGF-beta(2) gene. Exp Nephrol 10:374-82 |
| Schultz, Jo El J; Witt, Sandra A; Glascock, Betty J et al. (2002) TGF-beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II. J Clin Invest 109:787-96 |
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