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.
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.
|Rieger, Megan E; Zhou, Beiyun; Solomon, Nicola et al. (2016) p300/Î²-Catenin Interactions Regulate Adult Progenitor Cell Differentiation Downstream of WNT5a/Protein Kinase C (PKC). J Biol Chem 291:6569-82|
|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|
|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|
|Xing, Yiming; Wang, Runming; Li, Changgong et al. (2015) PTEN regulates lung endodermal morphogenesis through MEK/ERK pathway. Dev Biol 408:56-65|
|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 Î²-catenin and transforming growth factor-Î² 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-Ã½Ã½ 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|
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