Zemke, Anna Christine
(2007)
Roles for TGF-beta/BMP and beta-catenin signaling pathways in lung development and repair.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The conducting airway epithelium is lined with a heterogeneous population of secretory and ciliated cells. Inflammation and inhaled toxicants can damage the epithelial lining, which is rapidly repaired through a tissue stem cell-mediated process. Incomplete and disrupted repair contribute to the development of chronic lung disease. The signaling pathways that orchestrate airway epithelial repair are largely unknown. In the first part of the dissertation, the necessity for Wnt/â-catenin signaling in airway epithelial homeostasis and repair was determined. Wnt/â-catenin signaling regulates epithelial homeostasis in the intestine and skin, but the role of this pathway in the airways is unknown. This hypothesis was tested through the generation of mice airway-specific loss of â-catenin. A â-catenin null airway epithelium repaired normally in an in vivo injury model system. No defects in epithelial homeostasis or differentiation were seen in the absence of â-catenin. We concluded that â-catenin is not a principal regulator of airway homeostasis in the adult conducting airway epithelium. The second project determined the role of TGFâ/BMP signaling in airway branching morphogenesis, tumor suppression, and epithelial repair. Genetic deletion of Smad4 in the epithelium was used to block signaling through both the TGFâ and BMP pathways. Loss of Smad4-dependent signaling during embryogenesis markedly increased airway branching. These mice later developed adenomas, reflecting the role of Smad4 in lung tumor suppression. Surprisingly, epithelial repair was not influenced by loss of Smad-dependent signaling. These date indicated a role for TGFâ/BMP signaling in branching morphogenesis and tumor suppression, but not epithelial repair. The third project of this dissertation further characterized the molecular phenotype of the airway secretory cell population. Two ablation models were used to deplete secretory cells in vivo. Microarray analysis was performed following secretory cell ablation to identify genes that might be expressed within the secretory population. Four novel secretory cell markers were identified by this approach. In conclusion, this dissertation determined roles for Wnt/â-catenin and TGFâ/BMP signaling in the airway epithelium and further characterized the molecular repertoire of the airway secretory cell population.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Zemke, Anna Christine | acz2@pitt.edu | ACZ2 | |
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| ETD Committee: |
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| Date: |
20 September 2007 |
| Date Type: |
Completion |
| Defense Date: |
29 August 2007 |
| Approval Date: |
20 September 2007 |
| Submission Date: |
4 September 2007 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cell Biology and Molecular Physiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
beta-catenin; clara; lung; tgf-beta |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-09042007-123846/, etd-09042007-123846 |
| Date Deposited: |
10 Nov 2011 20:01 |
| Last Modified: |
15 Nov 2016 13:50 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9325 |
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