It is generally believed that alveolar epithelial type II (AT2) cells serve as progenitors of type I (AT1) cells in development and following injury to restore the alveolar gas exchange surface. However, the transcriptional programs that mediate differentiation between alveolar epithelial cell (AEC) phenotypes are almost entirely unknown. We have developed well-defined primary cell culture systems in which AEC transdifferentiation in vitro can be experimentally modulated, providing an excellent model with which to dissect molecular pathways that regulate transitions between AT2 and AT1 cell phenotypes. The transcription factor (TF) GATA-6 has been shown to be essential for AT1 cell differentiation during development. The goal of this proposal is to investigate the role of GATA-6 in regulating transitions between AT2 and AT1 cell phenotypes through reciprocal activation and repression of differentiation-related genes, with the long-range objective of understanding how regulation of AEC differentiation contributes to maintenance and repair of adult alveolar epithelium following injury. We hypothesize that: 1) activation and repression of cell type-specific genes that accompany transitions between AT1 and AT2 cell phenotypes in alveolar epithelium in adult lung are modulated by reciprocal up- or down-regulation/interactions of TF; 2) changes in the relative expression/activity of GATA-6 regulate transitions between AT2 and AT1 cell phenotypes; and 3) combinatorial interactions of GATA-6 with other cofactors or cell-restricted TF determine the state of AEC differentiation. We will capitalize on our established in vitro culture systems and success in isolating both AT2 and AT1 cells, together with expertise in characterizing AEC differentiation, to explore these hypotheses by addressing the following Specific Aims: 1) investigate the role of GATA-6 expression in regulation of AEC differentiated phenotype, 2) determine effects of modulating GATA-6 expression on AEC differentiated phenotype, and 3) investigate regulation of AEC differentiation by characterizing interactions of GATA-6 with cell-type specific genes and other cell-restricted TF. The role of GATA-6 in AEC differentiation will be elucidated by evaluating its expression in isolated and cultured AEC and in situ, modulating GATA-6 expression and assessing effects on AEC phenotype, and characterizing its interactions with and promoter occupancy of an AT1 cell-specific gene, aquaporin-5, in AT2 vs. AT1 cells. These studies will provide novel insights into molecular programming of AEC differentiation, which will form the basis for further studies to develop new therapeutic strategies for recovery from lung injury. ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Denholm, Elizabeth M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Southern California
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
Zip Code
Zhou, Beiyun; Buckley, Stephen T; Patel, Vipul et al. (2012) Troglitazone attenuates TGF-ýý1-induced EMT in alveolar epithelial cells via a PPARýý-independent mechanism. PLoS One 7:e38827
Zhou, Beiyun; Liu, Yixin; Kahn, Michael et al. (2012) Interactions between ?-catenin and transforming growth factor-? signaling pathways mediate epithelial-mesenchymal transition and are dependent on the transcriptional co-activator cAMP-response element-binding protein (CREB)-binding protein (CBP). J Biol Chem 287:7026-38
Yacobi, Nazanin R; Fazllolahi, Farnoosh; Kim, Yong Ho et al. (2011) Nanomaterial interactions with and trafficking across the lung alveolar epithelial barrier: implications for health effects of air-pollution particles. Air Qual Atmos Health 4:65-78
Fazlollahi, Farnoosh; Sipos, Arnold; Kim, Yong Ho et al. (2011) Translocation of PEGylated quantum dots across rat alveolar epithelial cell monolayers. Int J Nanomedicine 6:2849-57
Zhong, Qian; Zhou, Beiyun; Ann, David K et al. (2011) Role of endoplasmic reticulum stress in epithelial-mesenchymal transition of alveolar epithelial cells: effects of misfolded surfactant protein. Am J Respir Cell Mol Biol 45:498-509
Kim, Yong Ho; Fazlollahi, Farnoosh; Kennedy, Ian M et al. (2010) Alveolar epithelial cell injury due to zinc oxide nanoparticle exposure. Am J Respir Crit Care Med 182:1398-409
Yacobi, Nazanin R; Malmstadt, Noah; Fazlollahi, Farnoosh et al. (2010) Mechanisms of alveolar epithelial translocation of a defined population of nanoparticles. Am J Respir Cell Mol Biol 42:604-14
Flodby, Per; Borok, Zea; Banfalvi, Agnes et al. (2010) Directed expression of Cre in alveolar epithelial type 1 cells. Am J Respir Cell Mol Biol 43:173-8
Demaio, Lucas; Tseng, Wanru; Balverde, Zerlinde et al. (2009) Characterization of mouse alveolar epithelial cell monolayers. Am J Physiol Lung Cell Mol Physiol 296:L1051-8
Borok, Zea; Crandall, Edward D (2009) More life for a ""terminal"" cell. Am J Physiol Lung Cell Mol Physiol 297:L1042-4

Showing the most recent 10 out of 90 publications