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Roles for TGF-beta/BMP and beta-catenin signaling pathways in lung development and repair

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 (Unpublished)

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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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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Zemke, Anna Christineacz2@pitt.eduACZ2
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSchlatt, Stefanschlatt@pitt.eduSCHLATT
Committee MemberStripp, Barry
Thesis AdvisorBrodsky, Jefferyjbrodsky@pitt.eduJBRODSKY
Committee MemberKaminski, Naftali
Committee MemberOury, Timtdoury@pitt.eduTDOURY
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:, etd-09042007-123846
Date Deposited: 10 Nov 2011 20:01
Last Modified: 15 Nov 2016 13:50


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