This renewal application seeks funding to define a transcriptional network that determines AEC differentiation, goblet cell metaplasia/hyperplasia, and inflammation related to the pathogenesis of asthma, other chronic pulmonary disorders, and acute viral infection by rhinovirus. The application is based on novel data demonstrating the critical roles of the proposed transcriptional network that is centered on an Ets family member, SPDEF (SAM pointed domain ets-like factor) that regulates goblet cell differentiation and inflammatory processes in the lung. Our preliminary data demonstrate that differentiation of AECs in conducting airways is mediated by a cell intrinsic transcriptional program in which SPDEF and FOXA family members and TTF-1 (thyroid transcription factor-1, aka Nkx2.1) play fundamental roles. Preliminary data support the concept that Spdef drives mucus cell metaplasia, eosinophilic chemokine, and TH2 cytokine expression from AECs in response to allergens and rhinoviral infection. The application will utilize transgenic mouse models in which Spdef is deleted or expressed;bioinformatics, in vitro cultures of human bronchial epithelial cell (HBECs), and biochemistry to determine mechanisms by which SPDEF controls mucus metaplasia and innate immunity.
Aim 1 will identify the mechanisms by which the transcription factor SPDEF is regulated at transcriptional and post-transcriptional levels during mucus metaplasia induced by rhinovirus and aeroallergen exposure. Mechanisms controlling its regulation and function will be identified.
Aim 2 will test the hypothesis that SPDEF regulates transcription of genes critical for mucus cell differentiation, innate immunity, and inflammation i the respiratory epithelium, identifying transcriptional targets in AECs.
Aim 3 will identify physiological and inflammatory consequences of SPDEF in mouse models in vivo, identifying the effects of the network on pulmonary physiology, inflammatory responses, and tissue remodeling during viral infection and TH2 stimulation. The present application represents my laboratory's increasing interest in the transcriptional control of conducting airway epithelial cel differentiation in health and disease. These studies will provide insights into the pathogenesis of mucus cell metaplasia and hyperproduction associated with asthma, COPD, and acute infections that commonly complicate these disorders, providing the basis for the development of new strategies to diagnose and treat chronic respiratory diseases that are common causes of morbidity and mortality world- wide.

Public Health Relevance

Mucus cell metaplasia/hyperplasia, inflammation, and tissue remodeling accompany common chronic respiratory disorders, including asthma, CF, and COPD that, together, represent a significant health and economic burden worldwide. Mucus hyper-production represents a ubiquitous, if not noisome response to allergens and viral infections, the latter causing clinical exacerbations in patients with these chronic lung diseases. The present application will determine the role of a novel transcriptional network, mediated by SPDEF, which regulates mucus production that, in turn, influences lung inflammation and innate host defenses against microbial pathogens associated with common pulmonary disorders. The project will identify new mechanisms regulating airway epithelial homeostasis that will provide novel targets to diagnose and treat chronic pulmonary diseases affecting the airways.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL095580-05
Application #
8501840
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Banks-Schlegel, Susan P
Project Start
2009-04-01
Project End
2018-03-31
Budget Start
2013-04-15
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$503,189
Indirect Cost
$174,307
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Giridhar, Premkumar Vummidi; Bell, Sheila M; Sridharan, Anusha et al. (2016) Airway Epithelial KIF3A Regulates Th2 Responses to Aeroallergens. J Immunol 197:4228-4239
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:
Du, Yina; Guo, Minzhe; Whitsett, Jeffrey A et al. (2015) 'LungGENS': a web-based tool for mapping single-cell gene expression in the developing lung. Thorax 70:1092-4
Whitsett, Jeffrey A; Wert, Susan E; Weaver, Timothy E (2015) Diseases of pulmonary surfactant homeostasis. Annu Rev Pathol 10:371-93
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
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
Ishida, Naomasa; Fukazawa, Takuya; Maeda, Yutaka et al. (2015) A novel PI3K inhibitor iMDK suppresses non-small cell lung Cancer cooperatively with A MEK inhibitor. Exp Cell Res 335:197-206
Snowball, John; Ambalavanan, Manoj; Whitsett, Jeffrey et al. (2015) Endodermal Wnt signaling is required for tracheal cartilage formation. Dev Biol 405:56-70
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
Kamath-Rayne, Beena D; Du, Yina; Hughes, Maria et al. (2015) Systems biology evaluation of cell-free amniotic fluid transcriptome of term and preterm infants to detect fetal maturity. BMC Med Genomics 8:67

Showing the most recent 10 out of 39 publications