DOI
10.17077/etd.1wowmft3
Document Type
Dissertation
Date of Degree
Spring 2018
Access Restrictions
Access restricted until 07/03/2019
Degree Name
PhD (Doctor of Philosophy)
Degree In
Molecular Physiology and Biophysics
First Advisor
Michael J. Welsh
First Committee Member
Mark Stamnes
Second Committee Member
Robert Piper
Third Committee Member
Scott Moye-Rowley
Fourth Committee Member
Christopher Adams
Fifth Committee Member
Sheila Baker
Sixth Committee Member
Michael J. Welsh
Abstract
During embryogenesis, airway epithelial cells possess primary cilia, and HH signaling guides lung development. As epithelial cells mature, they produce hundreds of motile cilia and continue to produce the sonic hedgehog (SHH) ligand, which is found apically in the thin layer of liquid covering airways. However, whether ciliated airway cells express apical HH signaling components and what their function might be have remained unknown. Here we show that motile cilia are enriched for HH signaling proteins, including patched 1 and smoothened. These cilia are also enriched for proteins affecting cAMP-dependent signaling, including Gαi and adenylyl cyclase 5/6. Surprisingly, SHH in differentiated airway epithelia did not elicit the canonical SHH signaling pathway that regulates transcription during development. But instead, activating HH signaling decreases intracellular levels of cAMP, which reduces ciliary beat frequency and airway surface liquid pH, similar to changes that have been observed in the airway of people with chronic obstructive pulmonary disease (COPD). Furthermore, we observed that significant increase of SHH ligand expression in differentiated airway epithelia with COPD, suggesting a potential role of SHH signaling in the pathogenesis of airway disease. Collectively, our study indicates that airway cilia detect apical SHH to mediate airway physiology through noncanonical HH signaling. SHH may dampen defenses at the contact point between the environment and the lung, perhaps counterbalancing processes that stimulate airway defenses. This may suggest a potential role of SHH signaling in the pathogenesis of airway disease, such as COPD.
Keywords
Airway epithelia, Motile cilia, Sonic hedgehog signaling
Pages
xii, 93 pages
Bibliography
Includes bibliographical references (pages 81-93).
Copyright
Copyright © 2018 Suifang Mao
Recommended Citation
Mao, Suifang. "Motile cilia of human airway epithelia mediate noncanonical hedgehog signaling." PhD (Doctor of Philosophy) thesis, University of Iowa, 2018.
https://doi.org/10.17077/etd.1wowmft3
Comments
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