? This application seeks continuation of funding for years 14-19 for studies to elucidate the function and regulation of surfactant protein B in the developing and postnatal lung. This grant was initiated with the discovery of SP-B and its cDNA by this laboratory. The critical role of surfactant protein B in lung function and homeostasis was demonstrated through in vitro and in vivo studies. Newborn infants suffering from respiratory distress related to mutations or deficiency of SP-B were identified. Gene targeting and replacement studies in transgenic mice demonstrated the requirement of SP-B for lung function at birth, as well as in adult mice. Reduction of SP-B mRNA and protein to less than 50% resulted in severe abnormalities in respiratory physiology. However, the mechanisms and cellular responses involved in both regulation of SP-B and its function during injury, remain poorly understood. This application seeks to test the general hypothesis that factors regulating SP-B are critical to the maintenance of lung function in the perinatal and postnatal period, and that reduction or loss of SP-B results in stereotypic cellular and physiologic consequences involved in the pathogenesis of RDS and ARDS. We will identify 1) critical cis-acting elements and nuclear proteins mediating transcriptional control of the SP-B gene, 2) the role of TTF-1 phosphorylation and nuclear trafficking of TTF-1, via TAZ, 3) the precise temporal-spatial requirements of SP-B for postnatal respiratory function, and 4) the transcriptional responses of the lung to lethal and sublethal reductions in SP-B. We developed mice in which the human SP-B gene is conditionally replaced in the lung using a doxycycline regulatable lung specific element, completely rescuing the respiratory failure in SP-B gene targeted newborn and adult mice. With this model, temporal and spatial requirements for SP-B and its role in regulating alveolar homeostasis, including surfactant function, uptake, secretion, and tubular myelin formation will be discerned. Effects of severe reductions in SP-B on lung structure and function will be assessed. Transcriptional responses to decreased SP-B will be determined using RNA microarray, to identify the molecular pathways mediating or compensating for reduced SP-B/surfactant function in vivo. ? ?
| Besnard, Valérie; Matsuzaki, Yohei; Clark, Jean et al. (2010) Conditional deletion of Abca3 in alveolar type II cells alters surfactant homeostasis in newborn and adult mice. Am J Physiol Lung Cell Mol Physiol 298:L646-59 |
| Cardoso, Wellington V; Whitsett, Jeffrey A (2008) Resident cellular components of the lung: developmental aspects. Proc Am Thorac Soc 5:767-71 |
| Ikegami, Machiko; Falcone, Angelica; Whitsett, Jeffrey A (2008) STAT-3 regulates surfactant phospholipid homeostasis in normal lung and during endotoxin-mediated lung injury. J Appl Physiol 104:1753-60 |
| Matsuzaki, Yohei; Besnard, Valerie; Clark, Jean C et al. (2008) STAT3 regulates ABCA3 expression and influences lamellar body formation in alveolar type II cells. Am J Respir Cell Mol Biol 38:551-8 |
| Whitsett, Jeffrey A (2008) Hereditary disorders of surfactant homeostasis cause acute and chronic lung disease in infancy. Thorax 63:295-6 |
| Park, Kwon-Sik; Korfhagen, Thomas R; Bruno, Michael D et al. (2007) SPDEF regulates goblet cell hyperplasia in the airway epithelium. J Clin Invest 117:978-88 |
| Berclaz, Pierre-Yves; Carey, Brenna; Fillipi, Marie-Dominique et al. (2007) GM-CSF regulates a PU.1-dependent transcriptional program determining the pulmonary response to LPS. Am J Respir Cell Mol Biol 36:114-21 |
| Maeda, Yutaka; Dave, Vrushank; Whitsett, Jeffrey A (2007) Transcriptional control of lung morphogenesis. Physiol Rev 87:219-44 |
| Stahlman, Mildred T; Besnard, Valerie; Wert, Susan E et al. (2007) Expression of ABCA3 in developing lung and other tissues. J Histochem Cytochem 55:71-83 |
| Bry, Kristina; Whitsett, Jeffrey A; Lappalainen, Urpo (2007) IL-1beta disrupts postnatal lung morphogenesis in the mouse. Am J Respir Cell Mol Biol 36:32-42 |
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