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).

Comments

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Copyright

Copyright © 2018 Suifang Mao

Available for download on Wednesday, July 03, 2019

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