An intractable cell type in lung development is the secondary crest myofibroblast (SCMF). Our present understanding of SCMFs is limited to only a descriptive outline of their biology. SCMFs occupy a specific and important topography, being localized to the tip of the secondary crest structure. As such, they are critical to the process of alveolization referred to as the culmination of lung development. And yet largely due to lack of specific and tractable markers they remain poorly defined. In effect, what we know about these highly specialized mesodermally-derived cells is that they express Pdgfr? and ?Sma; produce elastin, and participate in alveolization. Thus elucidating their ontogeny, isolating them as a cel population for functional genomics analysis and manipulating their genetic repertoire to uncover their precise role in alveogenesis are center stage for understanding distal lung development. Importantly, there is widespread recognition that such analyses are badly needed if we are to effectively address neonatal (e.g. BPD) and adult (e.g. COPD) diseases of the lung. This application is specifically tailored to address these needs. In preliminary data we demonstrate that Gli1- creERT2 driver mice represent a valuable tool for identifying, isolating and lineage tracing of SCMFs in the lung. We propose the following hypothesis and utilize this novel tool to address the emergent specific aims: Hypothesis: Hedgehog signaling constitutes a key instructional pathway in commitment of multipotential mesenchymal cells to ?Sma-expressing (?Smpos) derivatives during lung development.
Specific Aim 1 : To Determine Whether Hedgehog Signaling is Necessary for Alveolar Formation.
Specific Aim 2. To Determine the Mechanism by which Lack of PDGFA Blocks the ontogeny of SCMF & Alveolization..
Specific Aim 3 : To Determine the Fate of SCMF in a Model of Hyperoxia-Induced Alveolar Hypoplasia.
Specific Aim 4 : To Determine the Genetic Signature of SCMF Progenitors by Transcriptomic Analysis.

Public Health Relevance

This project proposes to characterize the process of alveolar formation in a mouse model. The project uses specific genetic tools to elucidate the role of a specific cell type, known as secondary crest myofibroblasts that is critical to alveolar formation. Elucidating the mechanisms of alveolar formation is of great significance and relevance to respiratory disease in children and adult alike.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL122764-04
Application #
9392930
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Lin, Sara
Project Start
2015-01-01
Project End
2018-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Southern California
Department
Pediatrics
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Flodby, Per; Liebler, Janice M; Sunohara, Mitsuhiro et al. (2017) Region-specific role for Pten in maintenance of epithelial phenotype and integrity. Am J Physiol Lung Cell Mol Physiol 312:L131-L142
Chao, Cho-Ming; Yahya, Faady; Moiseenko, Alena et al. (2017) Fgf10 deficiency is causative for lethality in a mouse model of bronchopulmonary dysplasia. J Pathol 241:91-103
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
Liebler, Janice M; Marconett, Crystal N; Juul, Nicholas et al. (2016) Combinations of differentiation markers distinguish subpopulations of alveolar epithelial cells in adult lung. Am J Physiol Lung Cell Mol Physiol 310:L114-20
Li, Aimin; Ma, Shudong; Smith, Susan M et al. (2016) Mesodermal ALK5 controls lung myofibroblast versus lipofibroblast cell fate. BMC Biol 14:19
Xing, Yiming; Wang, Runming; Li, Changgong et al. (2015) PTEN regulates lung endodermal morphogenesis through MEK/ERK pathway. Dev Biol 408:56-65
Chao, Cho-Ming; El Agha, Elie; Tiozzo, Caterina et al. (2015) A breath of fresh air on the mesenchyme: impact of impaired mesenchymal development on the pathogenesis of bronchopulmonary dysplasia. Front Med (Lausanne) 2:27
Sureshbabu, Angara; Syed, Mansoor A; Boddupalli, Chandra Sekhar et al. (2015) Conditional overexpression of TGF?1 promotes pulmonary inflammation, apoptosis and mortality via TGF?R2 in the developing mouse lung. Respir Res 16:4
Li, Changgong; Bellusci, Saverio; Borok, Zea et al. (2015) Non-canonical WNT signalling in the lung. J Biochem 158:355-65
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