Two phenotypically different lung cells line the alveolar epithelium. Type I cells are the most susceptible to injury due to endogenous and exogenous insults. The injured alveolar epithelium can be repaired by the proliferation and differentiation of type II cells into type I cells. The same process occurs in turnover and development of normal alveolar epithelium. However, the molecular mechanisms for this process are poorly understood. Previous studies have focused on several particular genes such as surfactant proteins or T1 alpha during phenotypical change of lung cells. Global gene expression profiles during this process have not been examined. Our long-term goal is to understand the molecular mechanisms of the differentiation of alveolar epithelial cells. In the present proposal, we will examine gene expression profiles during the differentiation of alveolar epithelial cells using the DNA microarray technique. Model systems that will be used include alveolar epithelial cell culture, animal model for hyperoxia-induced rat lung injury and repair, and fetal lung development.
Specific Aim I will test the hypothesis that cell-specific genes are down- or up-regulated during the differentiation of alveolar epithelial cells. Novel markers for alveolar type I and type II cells will be identified, characterized, and used as biochemical markers for acute lung injury.
Specific Aim II will determine common gene expression patterns of alveolar epithelial cells during the remodeling of injured alveolar epithelium and fetal lung development using DNA microarray and cluster analysis. In addition, target genes that are important for the differentiation of alveolar epithelial cells will be identified and their functional significance will be tested.
Specific Aim III will test the hypothesis that the phenotypic change of alveolar epithelial cells is reversible based on the global gene expression using an alveolar epithelial cell signature DNA microarray. The results from this study will not only advance our understanding of cell differentiation, but also provide valuable directions toward therapeutic intervention of pulmonary diseases such as hyperoxia-induced lung injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071628-03
Application #
6901887
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Denholm, Elizabeth M
Project Start
2003-07-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
3
Fiscal Year
2005
Total Cost
$303,600
Indirect Cost
Name
Oklahoma State University Stillwater
Department
Physiology
Type
Schools of Veterinary Medicine
DUNS #
049987720
City
Stillwater
State
OK
Country
United States
Zip Code
74078
Mishra, Amarjit; Guo, Yujie; Zhang, Li et al. (2016) A Critical Role for P2X7 Receptor-Induced VCAM-1 Shedding and Neutrophil Infiltration during Acute Lung Injury. J Immunol 197:2828-37
Wang, Yang; Huang, Chaoqun; Chintagari, Narendranath Reddy et al. (2015) miR-124 regulates fetal pulmonary epithelial cell maturation. Am J Physiol Lung Cell Mol Physiol 309:L400-13
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
Wang, Yang; Huang, Chaoqun; Reddy Chintagari, Narendranath et al. (2013) miR-375 regulates rat alveolar epithelial cell trans-differentiation by inhibiting Wnt/?-catenin pathway. Nucleic Acids Res 41:3833-44
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
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

Showing the most recent 10 out of 42 publications