The lung airways form through a reiterative process of branching morphogenesis with concomitant cellular differentiation that is regulated, in part, through the activity of multiple signal transduction pathways. Accumulating evidence points to a role for both positive and negative signals from these pathways, which are regulated in a spatial and temporal manner during lung morphogenesis. The action of these pathways results in the distinct proximal-distal patterning observed in the lung airways, which is essential for the proper differentiation of airway epithelia into the active gas exchange interface in mammals. We have recently demonstrated a critical role for the Wnt signaling pathway in lung airway development and differentiation. Our studies show that inactivation of Wnt7b results in severe lung hypoplasia resulting from inhibited airway branching as well as defects in mesenchymal proliferation and type I cell differentiation. We have more recently demonstrated that inactivation of the canonical Wnt pathway in lung epithelia either by loss of (-catenin expression or expression of the Wnt inhibitor dkk1 leads to a loss of distal airway epithelium by acting upstream of essential transcriptional and signaling factors including N-myc, BMP4 and FGF signaling. Furthermore, we have identified the co-receptor complex in lung epithelium that transmits canonical Wnt signals through Wnt7b. Our hypothesis is that Wnt signaling plays a critical role in embryonic lung airway development, primarily through controlling patterning and differentiation of the airway epithelium. Since much is still not understood about the basic mechanisms underlying Wnt signaling in lung epithelial differentiation and development, we propose to further define the role of Wnt signaling by 1) determining the underlying in vivo mechanism involved in canonical Wnt signalings role in proximal-distal airway petterning, 2) determine the role of non-canonical Wnt signaling in the regulation of lung airway morphogenesis and differentiation, and 3) define the cellular mechanism by which both canonical and non-canonical Wnt signaling regulates lung epithelial cell differentiation, motility, and growth.
These aims will address the """"""""where"""""""", """"""""why"""""""", and """"""""how"""""""" Wnt signaling controls lung epithelial development, which is critical to a better understanding of how defective lung epithelial differentiation leads to human disease. Project narrative: Lung disease is a leading cause of death and morbidity in both neonates and adults. Understanding the molecular mechanisms that drive lung epithelial differentiation will allow for better design of future therapies for lung diseases. The current proposal uses novel state-of-the-art genetic models to determine the role of the Wnt signal transduction pathway in regulating lung epithelial differentiation with the ultimate goal of determining whether this pathway is a potential target of therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL087825-04
Application #
7989427
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Blaisdell, Carol J
Project Start
2007-12-10
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
4
Fiscal Year
2011
Total Cost
$475,414
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Swarr, Daniel T; Peranteau, William H; Pogoriler, Jennifer et al. (2018) Novel Molecular and Phenotypic Insights into Congenital Lung Malformations. Am J Respir Crit Care Med 197:1328-1339
Zacharias, William J; Frank, David B; Zepp, Jarod A et al. (2018) Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor. Nature 555:251-255
Morrisey, Edward E; Rustgi, Anil K (2018) The Lung and Esophagus: Developmental and Regenerative Overlap. Trends Cell Biol 28:738-748
Herriges, Michael J; Tischfield, David J; Cui, Zheng et al. (2017) The NANCI-Nkx2.1 gene duplex buffers Nkx2.1 expression to maintain lung development and homeostasis. Genes Dev 31:889-903
Zepp, Jarod A; Zacharias, William J; Frank, David B et al. (2017) Distinct Mesenchymal Lineages and Niches Promote Epithelial Self-Renewal and Myofibrogenesis in the Lung. Cell 170:1134-1148.e10
Stabler, Collin T; Morrisey, Edward E (2017) Developmental pathways in lung regeneration. Cell Tissue Res 367:677-685
Frank, David B; Peng, Tien; Zepp, Jarod A et al. (2016) Emergence of a Wave of Wnt Signaling that Regulates Lung Alveologenesis by Controlling Epithelial Self-Renewal and Differentiation. Cell Rep 17:2312-2325
Snitow, Melinda; Lu, MinMin; Cheng, Lan et al. (2016) Ezh2 restricts the smooth muscle lineage during mouse lung mesothelial development. Development 143:3733-3741
Wang, Yi; Frank, David B; Morley, Michael P et al. (2016) HDAC3-Dependent Epigenetic Pathway Controls Lung Alveolar Epithelial Cell Remodeling and Spreading via miR-17-92 and TGF-? Signaling Regulation. Dev Cell 36:303-15
Li, Shanru; Morley, Michael; Lu, MinMin et al. (2016) Foxp transcription factors suppress a non-pulmonary gene expression program to permit proper lung development. Dev Biol 416:338-46

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