Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


ucin1225203307.pdf (3.11 MB)

ETD Abstract Container

Abstract Header

The Retinoblastoma Tumor Supressor Protein is a Critical Regulator of Lung Epithelial Repair after Injury

Richie, Nicole
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1225203307

Abstract Details

2008, PhD, University of Cincinnati, Medicine : Pathobiology and Molecular Medicine.
Airway remodeling is associated with the vast majority of lung diseases including chronic obstructive pulmonary disease, asthma, and lung cancer. Epithelial regeneration is a key component in airway remodeling after injury. Accordingly, deregulated epithelial cell proliferation, survival, and differentiation play a prominent role in the pathogenesis of chronic lung disease. The lung epithelium is composed of specialized cell types that result from coordinate regulation of progenitor/stem cell proliferation and differentiation. The retinoblastoma gene product (Rb) regulates both proliferation and differentiation, and is inactivated in nearly all cases of lung cancer strongly implicating Rb as a critical regulator in the lung epithelium. The objective of this dissertation project was to test the hypothesis that Rb is essential for proper lung epithelial repair after injury. Rb ablation was targeted to the lung epithelium using a tetracycline regulated Cre/LoxP system, and epithelial injury was induced with naphthalene to mimic human lung disease. These studies demonstrate that although Rb is not required for establishing and maintaining epithelial quiescence during homeostasis, Rb is essential for establishing quiescence during epithelial repair after injury. Rb ablation during development and in the postnatal lung had similar effects providing evidence that timing of Rb loss was not critical to the phenotypic outcomes, and that the injury induced phenotype was not secondary to compensatory alterations occurring during development. After establishing this critical role for Rb in epithelial remodeling after a single episode of injury, Rb function was assessed in a chronic injury model to more closely mimic human lung disease. These studies led to the discovery of previously unknown effects of the highly utilized naphthalene injury model; namely naphthalene injury results in altered epithelial composition and subsequent inflammation. Importantly, Rb dependent sustained epithelial proliferation enhanced progenitor cell restoration after injury without resulting in tumor formation. Altogether, this dissertation project identifies a unique critical role for Rb in the context of epithelial remodeling after injury, and provides evidence that precise regulation of Rb function is important for balancing progenitor cell regeneration, and thus tissue renewal capacity, against the risk of developing cancer.
Kathryn Wikenheiser-Brokamp, M.D./Ph.D. (Advisor)
David Askew, Ph.D. (Committee Member)
Greg Boivin, D.V.M. (Committee Member)
Thomas Korfhagen, M.D./Ph.D. (Committee Member)
Erik Knudsen, Ph.D. (Committee Member)
186 p.
Molecular Biology; Oncology; Pathology
Retinoblastoma (Rb); Cre-LoxP; Lung injury; Lung progenitor and stem cells

Recommended Citations

Citations

  • Richie, N. (2008). The Retinoblastoma Tumor Supressor Protein is a Critical Regulator of Lung Epithelial Repair after Injury [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1225203307

    APA Style (7th edition)

  • Richie, Nicole. The Retinoblastoma Tumor Supressor Protein is a Critical Regulator of Lung Epithelial Repair after Injury. 2008. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1225203307.

    MLA Style (8th edition)

  • Richie, Nicole. "The Retinoblastoma Tumor Supressor Protein is a Critical Regulator of Lung Epithelial Repair after Injury." Doctoral dissertation, University of Cincinnati, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1225203307

    Chicago Manual of Style (17th edition)

ucin1225203307
598
© 2008, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.