Title: Airway Progenitor Cell Proliferation and Differentiation During Lung Repair This application responds to RFA-HL-12-006 to participate in a Consortium for the study of """"""""Lung Repair and Regeneration."""""""" The proposal seeks to establish a participating Center working closely with other national """"""""Consortium"""""""" members. Our proposed Center consists of faculty led by Dr. Jeffrey Whitsett at Cincinnati Children's Hospital IVIedical Center (CCHMC) and Dr. Philip Streeter at the Oregon Health and Science University (OHSU), who have established collaborations for the study of lung biology. Our Center provides four specific aims, all focused to transcriptional mechanisms controlling proliferation and differentiation of Ainway Epithelial Cell (AEC) progenitors.
The Aims also generate and provide new antibodies, gene expression data and transgenic models of broad application to the field of Pulmonary Biology and Medicine.
Aim 1 will elucidate the role of a novel transcriptional network controlling AEC progenitors and their differentiation in conducting airways, with focus to the role of a PAX9-centered transcriptional network in the regulation of basal cell proliferation and differentiation.
Aim 2 will produce, characterize and use monoclonal and polyclonal antibodies for the identification and purification of human and mouse AECs for study of lung repair and disease.
Aim 3 will define gene expression patterns and transcriptional regulators critical for AEC homeostasis with focus to PAX9 and associated factors.
This Aim will create and standardize expression and transcriptional databases for human and mouse AECs and iPS cells induced to specific ainway cell lineages.
Aim 4 will produce novel transgenic mice for the conditional deletion and addition of genes in conducting AECs, including those related to the study of PAX9. Preliminary data accompanying this application were produced via close collaborations and interactions between members of laboratories in multiple divisions at CCHMC in the fields of Pulmonary Biology, Developmental Biology, Hematology/Oncology, and Bioinformatics, as well as those at OHSU and the Oregon Stem Cell Center. Our investigators have long-standing commitments and success related to the building and sharing of useful technologies and reagents and have been long committed to training others to advance the field of pulmonary biology and medicine.

Public Health Relevance

This UOl grant seeks to provide (1) novel insights into the molecular and cellular control of AEC progenitors and their differentiation and (2) novel reagents, tools and procedures enabling scientific advancements of value to the field of pulmonary medicine.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZHL1-CSR-H (O1))
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Blaisdell, Carol J
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Cincinnati Children's Hospital Medical Center
United States
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Giridhar, Premkumar Vummidi; Bell, Sheila M; Sridharan, Anusha et al. (2016) Airway Epithelial KIF3A Regulates Th2 Responses to Aeroallergens. J Immunol 197:4228-4239
Xu, Yan; Mizuno, Takako; Sridharan, Anusha et al. (2016) Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis. JCI Insight 1:e90558
Davies, Elizabeth R; Kelly, Joanne F C; Howarth, Peter H et al. (2016) Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life. JCI Insight 1:
Whitsett, Jeffrey A; Wert, Susan E; Weaver, Timothy E (2015) Diseases of pulmonary surfactant homeostasis. Annu Rev Pathol 10:371-93
Snowball, John; Ambalavanan, Manoj; Cornett, Bridget et al. (2015) Mesenchymal Wnt signaling promotes formation of sternum and thoracic body wall. Dev Biol 401:264-75
Whitsett, Jeffrey A; Alenghat, Theresa (2015) Respiratory epithelial cells orchestrate pulmonary innate immunity. Nat Immunol 16:27-35
Snowball, John; Ambalavanan, Manoj; Whitsett, Jeffrey et al. (2015) Endodermal Wnt signaling is required for tracheal cartilage formation. Dev Biol 405:56-70
Rajavelu, Priya; Chen, Gang; Xu, Yan et al. (2015) Airway epithelial SPDEF integrates goblet cell differentiation and pulmonary Th2 inflammation. J Clin Invest 125:2021-31
Guo, Minzhe; Wang, Hui; Potter, S Steven et al. (2015) SINCERA: A Pipeline for Single-Cell RNA-Seq Profiling Analysis. PLoS Comput Biol 11:e1004575
Lange, Alexander W; Sridharan, Anusha; Xu, Yan et al. (2015) Hippo/Yap signaling controls epithelial progenitor cell proliferation and differentiation in the embryonic and adult lung. J Mol Cell Biol 7:35-47

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