? ? The objective of this project is to determine the role of laminin a5 in lung alveogenesis. Laminin a5, a component of basement membrane, has been shown to be important for lung lobar septation and formation of a visceral pleural basement membrane in early lung development using the laminin a5 null mouse. Because the laminin a5 null mouse has embryonic death, the role of laminin a5 in the latter stages of lung development, including alveolization, cannot be assessed. Using an allograft implant model, the laminin a5 null lung has abnormal development of the pre-alveolar saccules, hinting at abnormal alveolization.
The specific aims of this project are to determine the effect of lack of laminin a5 on alveolization during lung development and in alveolization in the adult lung using the post-pneumonectomy model. This will be achieved through generation and study of an inducible, lung-specific laminin a5 null mouse using the Tet-Cre system. In addition to characterization of alveolization during development and alveolization in adult lungs, domains of laminin a5 important for alveolization will also be identified using in vitro studies with alveolar epithelial cells from lung-specific laminin a5 null mice and peptides of domains of laminin a5. These studies will be of value in understanding and controlling the mechanisms behind lung growth. ? ? Implementation of these studies will provide the investigator with training from which an independent career in academic medicine can be constructed. The investigator will be supervised by Robert Senior, a leader in the study of lung biology, and Jeffrey Miner, a leader in basement membrane and laminin biology. The training will be enhanced by collaboration with Richard Pierce, who is an expert in the study of post-pneumonectomy lung growth. In addition, an advisory committee of highly regarded medical scientists will provide scientific and career advice. The research will be completed at Washington University, a world-renowned institution for medical and scientific research which will allow access to top scientists and the latest technologies. (End of Abstract) ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1-CSR-M (O1))
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Colombini-Hatch, Sandra
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Nguyen, Nguyet M; Pulkkinen, Leena; Schlueter, Jessica A et al. (2006) Lung development in laminin gamma2 deficiency: abnormal tracheal hemidesmosomes with normal branching morphogenesis and epithelial differentiation. Respir Res 7:28
Nguyen, Nguyet M; Senior, Robert M (2006) Laminin isoforms and lung development: all isoforms are not equal. Dev Biol 294:271-9
Nguyen, Nguyet M; Kelley, Diane G; Schlueter, Jessica A et al. (2005) Epithelial laminin alpha5 is necessary for distal epithelial cell maturation, VEGF production, and alveolization in the developing murine lung. Dev Biol 282:111-25