This application proposes to continue multidisciplinary studies of development, control and disorders of the pulmonary parenchyma. The objectives of the proposal are to examine some of the mechanisms involved in the formation and stabilization of the pulmonary parenchyma during development and post-natal life, and in states of health and disease. By stabilization we mean the integrated physiochemical and biological processes that develop and maintain alveolar architecture in an optimal state for pulmonary gas exchange. As in our past studies we emphasize investigations of alveolar epithelial development, functions of the lung surfactant system, and alveolar disease processes leading to infection and inflammation. The broad goals of the three inter-related projects proposed are: Project 1: Structure and function of surfactant proteins. To study the relationship between the structure of the surfactant proteins, specifically SP-D, and their functions in regulating the immune milieu of the alveolus. Project 2: Expression and role of CEACAM6 in the alveolus. To investigate the role of carcinoembryonic antigen-6 in alveolar innate immune defense, surfactant function, and epithelial response to acute lung injury. Project 3: Alveolar epithelial cell fates: mapping and regulation. To study alveolar epithelial cell lineages during development and regeneration and to elucidate novel regulatory molecules important to the process of alveolar epithelial differentiation. The overall purpose of these studies is to deepen our understanding of the processes underlying lung parenchymal stability and to contribute to new concepts and treatments for lung diseases associated with disorders of alveolar stability, growth, maturation, and repair after injury.

Public Health Relevance

Normal development and function of the alveolar region of the lung is critical to the exchange of oxygen and carbon dioxide, and therefore human health. Our proposal addresses fundamental questions of how the lung is protected from infection and inflammation and how the cellular lining of the lung is generated during development. The findings will contribute to a better understanding of lung injury and repair and potentially lead to new approaches to treatment and prevention.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Special Emphasis Panel (ZHL1-PPG-S (05))
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Lin, Sara
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Danhaive, Olivier; Chapin, Cheryl; Horneman, Hart et al. (2015) Surface film formation in vitro by infant and therapeutic surfactants: role of surfactant protein B. Pediatr Res 77:340-6
LaFemina, Michael J; Sutherland, Katherine M; Bentley, Trevor et al. (2014) Claudin-18 deficiency results in alveolar barrier dysfunction and impaired alveologenesis in mice. Am J Respir Cell Mol Biol 51:550-8
Gonzalez, Robert F; Dobbs, Leland G (2013) Isolation and culture of alveolar epithelial Type I and Type II cells from rat lungs. Methods Mol Biol 945:145-59
Chapin, Cheryl; Bailey, Nicole A; Gonzales, Linda W et al. (2012) Distribution and surfactant association of carcinoembryonic cell adhesion molecule 6 in human lung. Am J Physiol Lung Cell Mol Physiol 302:L216-25
Heine, Vivi M; Griveau, Amelie; Chapin, Cheryl et al. (2011) A small-molecule smoothened agonist prevents glucocorticoid-induced neonatal cerebellar injury. Sci Transl Med 3:105ra104
Gonzalez, Robert F; Allen, Lennell; Gonzales, Linda et al. (2010) HTII-280, a biomarker specific to the apical plasma membrane of human lung alveolar type II cells. J Histochem Cytochem 58:891-901
Gonzalez, Robert F; Allen, Lennell; Dobbs, Leland G (2009) Rat alveolar type I cells proliferate, express OCT-4, and exhibit phenotypic plasticity in vitro. Am J Physiol Lung Cell Mol Physiol 297:L1045-55
Mun, James J; Tam, Connie; Kowbel, David et al. (2009) Clearance of Pseudomonas aeruginosa from a healthy ocular surface involves surfactant protein D and is compromised by bacterial elastase in a murine null-infection model. Infect Immun 77:2392-8
Johnson, Meshell; Allen, Lennell; Dobbs, Leland (2009) Characteristics of Cl- uptake in rat alveolar type I cells. Am J Physiol Lung Cell Mol Physiol 297:L816-27
Vanderbilt, Jeff N; Allen, Lennell; Gonzalez, Robert F et al. (2008) Directed expression of transgenes to alveolar type I cells in the mouse. Am J Respir Cell Mol Biol 39:253-62

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