Airway remodeling accompanies common pulmonary disorders including asthma, chronic obstructive pulmonary disease, bronchopulmonary dysplasia and cystic fibrosis. Epithelial regeneration after injury is a key component in airway remodeling. Accordingly, cellular processes underlying the pathogenesis of lung disease include abnormalities in epithelial proliferation, differentiation and survival. The objective of the present proposal is to elucidate the role of the retinoblastoma family (Rb, p107 and p130) in lung morphogenesis and airway remodeling. The central hypothesis is that Rb family proteins act as distinct and critical regulators of epithelial proliferation, differentiation and survival both during development and in response to injury. Preliminary data demonstrate that Rb family proteins play an essential role in lung formation. In addition, Rb itself has an unexpected cell type specific function in the developing airway. Specifically, Rb is required for regulating neuroendocrine cell fate;cells known to play a central role in epithelial regeneration after injury. In contrast, other epithelial cell lineages are capable of compensating for loss of Rb function. This proposal is designed to 1) test the hypothesis that Rb deficiency results in deregulated epithelial regeneration after injury and subsequent development of lung disease, 2) test the hypothesis that timing of Rb inactivation in progenitor cells during development versus quiescent cells in the mature airway plays a fundamental role in determining phenotypic outcomes, and 3) elucidate the molecular mechanisms underlying cellular compensation for loss of Rb function. The studies will be performed in vivo by inducing Rb gene ablation in a temporal and lung epithelial specific manner in genetically modified mice. Effects of Rb family ablation (separately or in combination) on lung morphogenesis, cell cycle regulation and cell differentiation will be assessed. It is expected that these studies will result in a better understanding of epithelial biology and thus provide a solid foundation for development of novel therapies for lung disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Blaisdell, Carol J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cincinnati Children's Hospital Medical Center
United States
Zip Code
Akeno, Nagako; Reece, Alisa L; Callahan, Melissa et al. (2017) TRP53 Mutants Drive Neuroendocrine Lung Cancer Through Loss-of-Function Mechanisms with Gain-of-Function Effects on Chemotherapy Response. Mol Cancer Ther 16:2913-2926
Akeno, N; Miller, A L; Ma, X et al. (2015) p53 suppresses carcinoma progression by inhibiting mTOR pathway activation. Oncogene 34:589-99
Privette Vinnedge, L M; McClaine, R; Wagh, P K et al. (2011) The human DEK oncogene stimulates ?-catenin signaling, invasion and mammosphere formation in breast cancer. Oncogene 30:2741-52
Fuller, Kevin K; Richie, Daryl L; Feng, Xizhi et al. (2011) Divergent Protein Kinase A isoforms co-ordinately regulate conidial germination, carbohydrate metabolism and virulence in Aspergillus fumigatus. Mol Microbiol 79:1045-62
Hoskins, E E; Morris, T A; Higginbotham, J M et al. (2009) Fanconi anemia deficiency stimulates HPV-associated hyperplastic growth in organotypic epithelial raft culture. Oncogene 28:674-85
Wise-Draper, Trisha M; Mintz-Cole, Rachael A; Morris, Teresa A et al. (2009) Overexpression of the cellular DEK protein promotes epithelial transformation in vitro and in vivo. Cancer Res 69:1792-9
Simpson, David S; Mason-Richie, Nicole A; Gettler, Caitlin A et al. (2009) Retinoblastoma family proteins have distinct functions in pulmonary epithelial cells in vivo critical for suppressing cell growth and tumorigenesis. Cancer Res 69:8733-41
Wise-Draper, Trisha M; Morreale, Richard J; Morris, Teresa A et al. (2009) DEK proto-oncogene expression interferes with the normal epithelial differentiation program. Am J Pathol 174:71-81
Mason-Richie, Nicole A; Mistry, Meenakshi J; Gettler, Caitlin A et al. (2008) Retinoblastoma function is essential for establishing lung epithelial quiescence after injury. Cancer Res 68:4068-76