The significance of TGF? as a signaling molecule during development &disease can be hardly over-stated. Given the complexity of the signaling pathway, it is not surprising that there is a wide spectrum of versatility and selectivity in TGF? biological activity. Along the pathway, selective utilization of receptors is a potential mechanism for generating versatility. The in vivo role of the individual receptors in the lung mesoderm and epithelium has been a major interest in our group. In separate studies, we have used epithelial- or mesodermal-specific cre mice to inactivate Alk5 or T?R2, and examined the consequences in a highly systematic fashion. As a consequence, we now have an insight, however limited, into the role of each receptor in TGF? function. In the last cycle of this project, in addition to completing the original specific aims, we also collected preliminary data on the specific role of Alk5 in the lung mesoderm by genetic &molecular approaches. The preliminary findings collectively point to a unified underlying theme;that Alk5-mediated TGF? signaling is critical to progenitor/stem cell biology in various lung compartments. The simplified observed changes in the absence of mesodermal Alk5 function are, 1) reduced basal cell population in the trachea, 2) profoundly abnormal cartilage formation in the trachea, and 3) a major shift in the balance between lipofibroblasts versus myofibroblasts in the lung parenchyma. The phenotypes are fully penetrant, but the underlying mechanisms remain unknown. Elucidating these mechanisms is the goal of this application. Hypothesis: Mesodermal Alk5-mediated TGF? signaling controls the emergence/maintenance or differentiation of progenitor/stem cells in the lung. We will test the validity of this hypothesis by the following specific aims:
Specific Aim 1 : To Determine The Mechanisms by Which Inactivation of Alk5 in The Pulmonary Mesoderm Depletes Basal Cells.
Specific Aim 2 : To Determine The Role of Alk5 in Tracheal Morphogenesis.
Specific Aim 3 : To Determine Potential Phenotype Plasticity in Alk5-Regulated Lipofibroblast versus Myofibroblast Differentiation.
Specific Aim 4 : To Determine Whether Pulmonary Fibrosis Can be Rescued or Contained (i.e., Limited) by Inactivation of Alk5 &Trans-Differentiation of Activated Myofibroblasts to Lipofibroblasts. By completion of this work, we hope to have unraveled the specific role played by Alk5-mediated TGF? signaling in the ontogeny of key epithelial and mesenchymal progenitor/stem cell populations in the trachea and the lung parenchyma. The studies proposed here also offer the unique opportunity of examining, from a novel perspective the specific role of Alk5 in pathogenesis of pulmonary fibrosis in a mouse model.

Public Health Relevance

This project proposes to characterize the process of progenitor/stem cell differentiation in a mouse model. The project uses specific genetic tools to elucidate the role of a specific signaling molecule; known as Transforming Growth Factor beta (TGF?) and its receptor; Alk5 during lung development and also in pathogenesis of a lung disease known as pulmonary fibrosis. Elucidating the mechanisms of TGF? function is of great significance and relevance to respiratory diseases in adults and children.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Lin, Sara
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University of Southern California
Schools of Medicine
Los Angeles
United States
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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
Li, Aimin; Ma, Shudong; Smith, Susan M et al. (2016) Mesodermal ALK5 controls lung myofibroblast versus lipofibroblast cell fate. BMC Biol 14:19
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
Xing, Yiming; Wang, Runming; Li, Changgong et al. (2015) PTEN regulates lung endodermal morphogenesis through MEK/ERK pathway. Dev Biol 408:56-65
Al Alam, Denise; El Agha, Elie; Sakurai, Reiko et al. (2015) Evidence for the involvement of fibroblast growth factor 10 in lipofibroblast formation during embryonic lung development. Development 142:4139-50
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
Li, Aimin; Chan, Belinda; Felix, Juan C et al. (2013) Tissue-dependent consequences of Apc inactivation on proliferation and differentiation of ciliated cell progenitors via Wnt and notch signaling. PLoS One 8:e62215
Li, Changgong; Li, Aimin; Xing, Yiming et al. (2013) Apc deficiency alters pulmonary epithelial cell fate and inhibits Nkx2.1 via triggering TGF-beta signaling. Dev Biol 378:13-24
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

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