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.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-09042007-123846 |
| Date | 20 September 2007 |
| Creators | Zemke, Anna Christine |
| Contributors | Stefan Schlatt, PhD, Tim Oury, MD PhD, Barry R. Stripp, PhD, Naftali Kaminski, MD, Jeffery Brodsky, PhD |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-09042007-123846/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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