application): Lung surfactant is a surface active material that stabilizes the alveoli. It is synthesized and secreted by lung epithelial type II cells. Earlier signal transduction events prior to activation of protein kinases are well established in lung surfactant secretion. However, two essential steps involved in the later stages of secretory processes, including the transport of lamellar bodies to and fusion with the plasma membrane, have not been widely described. The long-term objective of this proposed project is to elucidate the molecular mechanisms of lung surfactant secretion from type II cells. Previous studies indicate that annexin II, an F-actin and phospholipid-binding protein, is a critical component in membrane fusion during surfactant secretion. In a continuation of exploring mechanisms of annexin II-mediated fusion of lamellar bodies with plasma membrane, SNARE proteins are now included as part of the molecular machinery for exocytosis of lamellar bodies.
Specific Aim 1 of the present application is to establish functional roles of SNARE proteins in lung surfactant secretion using various techniques including reconstitution from permeabilized type II cells, neutrotoxin effects, antibody neutralization, peptide inhibition and antisense oligonucleotides.
Specific Aim 2 will be achieved by determining physical and functional interactions of annexin II with SNARE proteins in type II cells.
Specific Aim 3 is to investigate another role of annexin II in surfactant secretion, i.e. facilitating reorganization of cytoskeleton and thus the transport of lamellar bodies from the base of the cells to the apex. Finally, Specific Aim 4 is to examine two novel post-translational modifications of annexin II, S-nitrosylation and nitration, and their effects on lung surfactant secretion. Deficiency of lung surfactant is the cause of respiratory distress syndrome in premature infants. Accomplishing the goals of this proposal will advance the understanding of molecular mechanisms of lung surfactant secretion and may give a valuable insight to the therapy of pulmonary diseases such as neonatal respiratory distress syndrome.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL052146-08
Application #
6389355
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Garfinkel, Susan J
Project Start
1995-07-01
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
8
Fiscal Year
2001
Total Cost
$257,371
Indirect Cost
Name
Oklahoma State University Stillwater
Department
Physiology
Type
Schools of Veterinary Medicine
DUNS #
City
Stillwater
State
OK
Country
United States
Zip Code
74078
Guo, Yujie; Mishra, Amarjit; Howland, Emily et al. (2015) Platelet-derived Wnt antagonist Dickkopf-1 is implicated in ICAM-1/VCAM-1-mediated neutrophilic acute lung inflammation. Blood 126:2220-9
Guo, Y; Mishra, A; Weng, T et al. (2014) Wnt3a mitigates acute lung injury by reducing P2X7 receptor-mediated alveolar epithelial type I cell death. Cell Death Dis 5:e1286
Kang, Kang; Peng, Xiao; Zhang, Xiaoying et al. (2013) MicroRNA-124 suppresses the transactivation of nuclear factor of activated T cells by targeting multiple genes and inhibits the proliferation of pulmonary artery smooth muscle cells. J Biol Chem 288:25414-27
Wang, Pengcheng; Howard, Marcia D; Zhang, Honghao et al. (2012) Characterization of VAMP-2 in the lung: implication in lung surfactant secretion. Cell Biol Int 36:785-91
Weng, Tingting; Mishra, Amarjit; Guo, Yujie et al. (2012) Regulation of lung surfactant secretion by microRNA-150. Biochem Biophys Res Commun 422:586-9
Mishra, Amarjit; Chintagari, Narendranath Reddy; Guo, Yujie et al. (2011) Purinergic P2X7 receptor regulates lung surfactant secretion in a paracrine manner. J Cell Sci 124:657-68
Zhang, Honghao; Mishra, Amarjit; Chintagari, Narendranath Reddy et al. (2010) Micro-RNA-375 inhibits lung surfactant secretion by altering cytoskeleton reorganization. IUBMB Life 62:78-83
Chintagari, Narendranath Reddy; Mishra, Amarjit; Su, Lijing et al. (2010) Vacuolar ATPase regulates surfactant secretion in rat alveolar type II cells by modulating lamellar body calcium. PLoS One 5:e9228
Weng, Tingting; Liu, Lin (2010) The role of pleiotrophin and beta-catenin in fetal lung development. Respir Res 11:80
Bhaskaran, Manoj; Wang, Yang; Zhang, Honghao et al. (2009) MicroRNA-127 modulates fetal lung development. Physiol Genomics 37:268-78

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