A functional surfactant is critically required for normal respiration. The thin blood-gas barrier that includes the alveolar surfactant film must also be maintained free of chronic inflammation, a challenge in the face of daily exposure to thousands of liters of potentially contaminated air. The surfactant proteins, initially characterized on the basis of lipid-binding and biophysical activity, appear to contribute to both surfactant homeostasis and lung stability and a multilayered alveolar immune defense. Our broad objective is to provide a more mechanistic understanding of how the surfactant proteins perform these dual roles and their relative physiological significance. Our studies may ultimately be relevant to diseases directly linked to abnormal surfactant homeostasis such as acute respiratory distress syndromes (too little) and alveolar proteinosis (too much) as well as chronic inflammatory diseases such as BPD and COPD. We propose to test the general hypothesis that specific ligand recognition by discrete sequences and conformations of surfactant proteins A and D mediates dual and sometimes overlapping functions in surfactant physiology and host defense. Our study design is based on the truism that structure begets function. We will first characterize the structural basis of specific protein-ligand interactions and then explore the role of these interactions in alveolar physiology using a sequence of functional experiments. We will start with site-specific protein mutagenesis and in vitro biochemical and cellular assays and progress to studies in vivo using transgenic mouse models.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL024075-30
Application #
7637808
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
30
Fiscal Year
2008
Total Cost
$423,122
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Barrette, Anne Marie; Roberts, Jessica K; Chapin, Cheryl et al. (2016) Antiinflammatory Effects of Budesonide in Human Fetal Lung. Am J Respir Cell Mol Biol 55:623-632
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
Vanderbilt, Jeff N; Gonzalez, Robert F; Allen, Lennell et al. (2015) High-efficiency type II cell-enhanced green fluorescent protein expression facilitates cellular identification, tracking, and isolation. Am J Respir Cell Mol Biol 53:14-21
Gonzales, Linda W; Gonzalez, Robert; Barrette, Anne Marie et al. (2015) Expression of Carcinoembryonic Cell Adhesion Molecule 6 and Alveolar Epithelial Cell Markers in Lungs of Human Infants with Chronic Lung Disease. J Histochem Cytochem 63:908-21
Raymond, Wilfred W; Xu, Xiang; Nimishakavi, Shilpa et al. (2015) Regulation of hepatocyte growth factor in mice with pneumonia by peptidases and trans-alveolar flux. PLoS One 10:e0125797
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

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