Diseases of impaired gas exchange, such as emphysema and lung fibrosis, are prevalent, clinically burdensome ,and difficult to treat. Because lung transplantation remains the only definitive treatment option for these diseases, much interest has been focused upon understanding the cellular and molecular basis of alveolar formation. As the current knowledge of mammalian lung alveolization is quite limited, this grant is directed towards exploring the mechanism of impaired alveolar septation in mouse models in an effort to understand the requirements of normal septation. The PI has recently observed distal airspace enlargement in two strains of fibrillin-I deficient mice and has found that TGF-beta is a critical mediator of this defect. The first objective is to determine the natural history of impaired septation in three fibrillin-1 defective mouse models. This pursuit should establish whether septation defects may represent important risk factors for the development of emphysema and pulmonary fibrosis. The natural history of the alveolization defects in these models will be correlated with the evolution of aberrant TGF-beta signaling previously observed in two of the models. The second objective is to identify the pulmonary morphologic aberrations which precede the observed septation defects in an effort to reveal critical mediators of septation. Several approaches will be employed to establish whether abnormalities in pulmonary vascular development, matrix composition, or both underlie the disruptions in septation. The final objective is to use chip-based gene expression profiling of murine lung to identify novel and important mediators of septation. The PI of this project is an instructor in the Department of Medicine. She is committed to a career in academic medicine and plans to spend 80 percent of her time in research pursuits. She has had previous training in signal transduction and, more recently, the use of transgenic mouse models to probe human disease. She now wants to expand her research interests to investigating mammalian lung development. To achieve this, she will take sponsored courses on murine development and attend lectures in the developmental genetics department at Johns Hopkins School of Medicine. The environment at Johns Hopkins provides several esteemed scientists who can provide guidance in the use of mouse models to probe lung pathology and developmental aberrations. Their involvement as well as a formal education program in both the Division of Pulmonary Medicine and Institute of Genetic Medicine should facilitate the achievement of her stated research objectives as well as aid in her development into a fully independent investigator.
| Podowski, Megan; Calvi, Carla L; Cheadle, Christopher et al. (2009) Complex integration of matrix, oxidative stress, and apoptosis in genetic emphysema. Am J Pathol 175:84-96 |
| Neptune, Enid R; Podowski, Megan; Calvi, Carla et al. (2008) Targeted disruption of NeuroD, a proneural basic helix-loop-helix factor, impairs distal lung formation and neuroendocrine morphology in the neonatal lung. J Biol Chem 283:21160-9 |
