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Signal Transduction and Cellular Differentiation in Airway Epithelium

Leahy, Rachel A.
http://rave.ohiolink.edu/etdc/view?acc_num=kent1352673026

Abstract Details

2012, PHD, Kent State University, College of Arts and Sciences / School of Biomedical Sciences.
The airway epithelium is a strictly regulated tissue requiring constant signal transduction to maintain cell homeostasis and health. Regulation of cellular metabolism and immune functioning are crucial in airway epithelial cells, which undergo fluctuations in oxygen content and endure frequent exposure to external toxins, irritants and pathogens. Here, we hypothesized that signal transduction of cell metabolic and host immune response pathways and the interaction between them regulate the structure and function in airway epithelium. To investigate this, we utilized several different model systems. We examined dysregulation of nitric oxide (NO) in nasal polyps and found the decrease in NO metabolites was due to abnormalities of nitric oxide metabolism including an upregulation in cell signal transduction pathways and diminished superoxide dismutase (SOD) activity, which likely resulted in altered regulation of growth and defective immune functioning in nasal polyposis. In an immortalized airway epithelial cell line (A549), we investigated the effects of a siRNA knockdown of AP-1 transcription factor c-Fos on inducible nitric oxide synthase (iNOS) activation and found that the knockdown resulted in a decrease in iNOS gene induction and NO synthesis in cytokine-stimulated lung epithelial cells as a result of less c-Fos/c-Jun heterodimer binding to the iNOS AP-1u DNA binding site, resulting in impaired immune response. Finally, we discovered that a crucial regulator of cell metabolism, hypoxia-inducible factor 1α (HIF1α), is increased in murine airway epithelial cells exposed to air in an organotypic cell culture system, which appears to allow differentiation of the flat cell monolayer back into specialized cell types including, basal, goblet and ciliated cells. Overall, the studies here highlight how the interactions between cell metabolism and immune response signal transduction pathways affect the structure and function of the airway epithelium.
Serpil Erzurum, MD (Committee Chair)
Gail Fraizer, PhD (Committee Member)
Christopher Woolverton, PhD (Committee Member)
Suzy Comhair, PhD (Committee Member)
Angela Ridgel, PhD (Committee Member)
134 p.
Biomedical Research
cellular differentiation, signal transduction, nitric oxide, c-Fos, AP-1, HIF1&945; , air-liquid interface

Recommended Citations

Citations

  • Leahy, R. A. (2012). Signal Transduction and Cellular Differentiation in Airway Epithelium [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1352673026

    APA Style (7th edition)

  • Leahy, Rachel. Signal Transduction and Cellular Differentiation in Airway Epithelium. 2012. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1352673026.

    MLA Style (8th edition)

  • Leahy, Rachel. "Signal Transduction and Cellular Differentiation in Airway Epithelium." Doctoral dissertation, Kent State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=kent1352673026

    Chicago Manual of Style (17th edition)

kent1352673026
1,544
© 2012, all rights reserved.
This open access ETD is published by Kent State University and OhioLINK.
Release 3.2.12