The studies in this application are designed to investigate the role of PTEN, a phosphatase about which very little is known in the lung. Deleted in many human cancers, Pten was initially thought to be a cancer suppressor gene. Its stellar role however, has emerged only recently as a key regulator of Progenitor/Stem cell homeostasis in various tissues including the brain and the gut. Preliminary data in this application show that epithelial deletion of Pten using a novel Nkx2.1-cre leads to expansion of the cells within the bronchioalveolar duct junction BADJ, a known lung Progenitor/Stem cell niche. Based on this finding future studies will be based on the HYPOTHESIS that """"""""Pten regulates the pool of lung Progenitor/Stem cell population residing within the BADJ niche"""""""".
Three Specific Aims will test the hypothesis.
Specific Aim 1. To Characterize Functional Properties of Pten(d/d) Epithelial Cells.
Specific Aim 2. To Determine the Role of AKT and ?-Catenin in the Ptend/d lung Phenotype Specific Aim 3. To Determine the Role of Pten in the Lung Mesenchyme:
These Specific Aims represent a thorough and mechanistic analysis of the functional role of Pten in the lung and one of its disorders, pulmonary fibrosis.

Public Health Relevance

This is a proposal to study a gene named Pten which controls the number of Progenitor/Stem cells in the lung. The studies address the specific role of Pten in a serious lung condition known as Pulmonary Fibrosis for which no treatment currently exists other than transplantation. The long-term goal of this project is to learn enough about Pten to be able to modify its function and therefore prevent or treat lung disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-RES-B (02))
Program Officer
Lin, Sara
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Southern California
Schools of Medicine
Los Angeles
United States
Zip Code
Flodby, Per; Kim, Yong Ho; Beard, LaMonta L et al. (2016) Knockout Mice Reveal a Major Role for Alveolar Epithelial Type I Cells in Alveolar Fluid Clearance. Am J Respir Cell Mol Biol 55:395-406
Rieger, Megan E; Zhou, Beiyun; Solomon, Nicola et al. (2016) p300/?-Catenin Interactions Regulate Adult Progenitor Cell Differentiation Downstream of WNT5a/Protein Kinase C (PKC). J Biol Chem 291:6569-82
Xing, Yiming; Wang, Runming; Li, Changgong et al. (2015) PTEN regulates lung endodermal morphogenesis through MEK/ERK pathway. Dev Biol 408:56-65
Li, Changgong; Li, Min; Li, Sha et al. (2015) Progenitors of secondary crest myofibroblasts are developmentally committed in early lung mesoderm. Stem Cells 33:999-1012
Li, Guanglei; Flodby, Per; Luo, Jiao et al. (2014) Knockout mice reveal key roles for claudin 18 in alveolar barrier properties and fluid homeostasis. Am J Respir Cell Mol Biol 51:210-22
Kage, Hidenori; Flodby, Per; Gao, Danping et al. (2014) Claudin 4 knockout mice: normal physiological phenotype with increased susceptibility to lung injury. Am J Physiol Lung Cell Mol Physiol 307:L524-36
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
DeMaio, Lucas; Buckley, Stephen T; Krishnaveni, Manda S et al. (2012) Ligand-independent transforming growth factor-ýý type I receptor signalling mediates type I collagen-induced epithelial-mesenchymal transition. J Pathol 226:633-44
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
Minoo, Parviz; Li, Changgong (2010) Cross-talk between transforming growth factor-beta and Wingless/Int pathways in lung development and disease. Int J Biochem Cell Biol 42:809-12

Showing the most recent 10 out of 35 publications