Genomes and Genes
Mechanism of Lung Development and Injury
Principal Investigator: PARVIZ MINOO MINOO
Affiliation: University of Southern California
Abstract: DESCRIPTION (provided by applicant): Transforming growth factors-[unreadable] are secreted polypeptides that render both physiological and pathological functions. Two receptor tyrosine kinases, T[unreadable]RI and T[unreadable]RII mediate the impact of TGF-[unreadable] signaling on the cell surface. Functional specificity and differences between the two receptors, subsequent to ligand binding have not been rigorously and mechanistically addressed in lung development and disease. We have found that TGF-[unreadable] signaling through the T[unreadable]RII plays a critical role in both morphogenesis and injury in the lung. In the mesenchyme, we found T[unreadable]RII to be required for normal epithelial-mesenchymal communication through Shh. In the epithelium, signaling through T[unreadable]RII regulates alveolar formation, and is required in Bleomycin-induced lung injury. Based on these concepts, we have formulated the following hypothesis: HYPOTHESIS: Normal lung development and Bleomycin-induced lung injury are dependent on TGF-[unreadable] signaling through T[unreadable]RII. The latter hypothesis is supported by the available data and some of its predictions are directly testable by the following four Specific Aims: Specific aim 1. To Determine the Mechanism of Cross-Talk Between Shh &TGF-[unreadable] Signaling Pathways. Specific aim 2. To Identify Components of the TGF-[unreadable] Pathway That Mediate the Cross-Talk With the Shh Pathway. Specific aim 3. To Determine the Potential Role of Epithelial T[unreadable]RII in Pathogenesis of Bleomycin-Induced Murine Model of Pulmonary Fibrosis. Health Relevance: TGF-[unreadable] is implicated in many lung diseases including Pulmonary Fibrosis and Bronchopulmonary Dysplasia. To our knowledge, the studies proposed in this application are the first to address, cell-specifically (epithelial versus mesenchymal) the contributions of signaling through T[unreadable]RII to pathogenesis of lung injury. PUBLIC HEALTH RELEVANCE: This project will use specific genetic tools to study the role of TGF-[unreadable] during lung development and in pathogenesis of neonatal and adult chronic diseases.
Funding Period: ----------------2009 - ---------------2014-
more information: NIH RePORT
- Apc deficiency alters pulmonary epithelial cell fate and inhibits Nkx2.1 via triggering TGF-beta signalingChanggong Li
Department of Pediatrics, USC Keck School of Medicine and Childrens Hospital Los Angeles, Los Angeles, CA 90033, USA
Dev Biol 378:13-24. 2013..Therefore, our studies revealed an important mechanism involving Apc and TGF-beta signaling in regulating the key transcriptional factor, Nkx2.1, for lung epithelial progenitor cell fate determination...
- Tissue-dependent consequences of Apc inactivation on proliferation and differentiation of ciliated cell progenitors via Wnt and notch signalingAimin Li
Division of Newborn Medicine, Department of Pediatrics, Los Angeles County University of Southern California Medical Center, Keck School of Medicine of USC, Los Angeles, California, United States of America
PLoS ONE 8:e62215. 2013..In sum, the present comparative analysis reveals the tissue-dependent consequences of Apc inactivation on proliferation and differentiation of ciliated cell progenitors by coordinating Wnt and Notch signaling...
- Cross-talk between transforming growth factor-beta and Wingless/Int pathways in lung development and diseaseParviz Minoo
Division of Neonatology, Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA
Int J Biochem Cell Biol 42:809-12. 2010..Understanding the mechanics and the physiological implications of this cross-talk is necessary for therapeutic or preventive targeting of either TGFbeta or Wnt signaling pathways...
- Epithelium-specific deletion of TGF-β receptor type II protects mice from bleomycin-induced pulmonary fibrosisMin Li
Division of Neonatology, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
J Clin Invest 121:277-87. 2011..To our knowledge, these findings are the first to demonstrate a specific role for TGF-β signaling in the lung epithelium in the pathogenesis of pulmonary fibrosis...
- Role of endoplasmic reticulum stress in epithelial-mesenchymal transition of alveolar epithelial cells: effects of misfolded surfactant proteinQian Zhong
Will Rogers Institute Pulmonary Research Center, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033, USA
Am J Respir Cell Mol Biol 45:498-509. 2011..These results demonstrate that ER stress induces EMT in AECs, at least in part through Src-dependent pathways, suggesting a novel role for ER stress in fibroblast accumulation in pulmonary fibrosis...
- Ligand-independent transforming growth factor-β type I receptor signalling mediates type I collagen-induced epithelial-mesenchymal transitionLucas DeMaio
Will Rogers Institute Pulmonary Research Center, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Southern California, CA 90033, USA
J Pathol 226:633-44. 2012....
- Interactions between β-catenin and transforming growth factor-β signaling pathways mediate epithelial-mesenchymal transition and are dependent on the transcriptional co-activator cAMP-response element-binding protein (CREB)-binding protein (CBP)Beiyun Zhou
Will Rogers Institute Pulmonary Research Center, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Southern California, Los Angeles, California 90033, USA
J Biol Chem 287:7026-38. 2012..These findings suggest a new therapeutic approach to pulmonary fibrosis by specifically uncoupling CBP/catenin-dependent signaling downstream of TGF-β...