Research Interests
a. p53 expression and lung fibrosis. Our laboratory has demonstrated expression of the p53 tumor suppressor protein at sites of fibrotic lesions after inhalation exposure of rodents to asbestos. To characterize p53 function in this rodent model of asbestos-induced pulmonary fibrosis, we prepared transgenic mice that express a dominant negative mutant form of p53 from the surfactant protein C promoter (SPC-DNp53 mice). These animals with inhibited p53 function in the lung epithelium appear to display reduced fibrogenesis post-exposure to asbestos. We postulate that p53-mediated apoptosis in asbestos-exposed mice contributes to injury of the lung epithelium, which can be ameliorated by inhibition of p53 function in these cells. In support of this postulate, the SPC-DNp53 mice are resistant to a lethal dose of a recombinant adenovirus that expresses TGF-ß, a major mediator of lung fibrosis. In contrast to these results, exposure of the SPC-DNp53 mice to bleomycin by intratracheal instillation produces more pronounced fibrogenesis than that in simultaneously exposed nontransgenic littermates. We suggest that p53-mediated activation of DNA repair protects the lung epithelium from the extensive DNA damage induced by bleomycin.
b. p53 and malignant conversion. A strong correlation exists between mutations in the p53 gene and malignant conversion. The phenotypic alterations of the SPC-DNp53 mice described above are consistent with disrupted p53 function in the epithelial cells of the small airways and the peripheral lung. This animal model is being used to study lung carcinogenesis induced by inhaled agents linked to human lung cancer, i.e. cigarette smoke and asbestos, to model the human disease in mice.
c. p53 mediated regulation of PCNA expression. One of the p53 target genes, proliferating cell nuclear antigen, PCNA, encodes a protein that functions in both DNA replication and repair. Accordingly, PCNA is expressed in cells exposed to mitogens or genotoxic stress. A body of evidence indicates that p53 can activate or repress transcription of the PCNA gene. The various roles of PCNA and the large number of PCNA interacting proteins, suggest that modulation of PCNA levels by p53 may integrate various cellular responses to stress. We are evaluating the molecular mechanisms leading to activation of the PCNA expression in models of lung injury and carcinogenesis.
d. Marrow-derived stromal cells in lung cancer therapy. Adult stem cells or marrow-derived stromal cells (MSCs) have great appeal as delivery vehicles for therapeutic gene products. MSCs can be easily isolated from any individual, rapidly expanded in cell culture and readily transduced ex vivo with genes that can produce a therapeutic benefit. Similar to wound healing, tumors stimulate expansion of stromal tissue. In accord with this stroma-promoting characteristic, it is hypothesized that lung tumors establish a microenvironment that promotes engraftment of MSCs. To test this hypothesis, MSCs are delivered by tail vein to lung tumor-bearing mice. Engraftment of MSCs delivered once or multiple times is quantified by measuring the activity of a MSC-specific reporter transgene in the tumor and adjacent normal tissue. Ionizing radiation is used to injure the tumor and thereby promote MSC engraftment. These studies will determine the feasibility of using MSCs in lung cancer therapeutics.
Selected Publications:
Nelson A., Mendoza T., Hoyle G.W., Brody A.R., Fermin C. and Morris G.F. Enhancement of fibrogenesis by the p53 tumor supressor protein in asbestos-exposed rodents. Chest 120: 33S-34S (2001).
Ghosh, S., Mendoza, T., Ortiz, L.A., Hoyle, G.W., Fermin, C.D., Brody, A.R., Friedman, M. and Morris, G.F. Enhanced bleomycin sensitivity in mice expressing dominant negative p53 from the surfactant protein C promoter. American Journal of Respiratory and Critical Care Medicine 166: 890-897 (2002).
Shan, B., Xu, J., Zhuo, Y., Morris, C.A. and Morris, G.F. Induction of p53-dependent activation of the human PCNA gene in chromatin by ionizing radiation. Journal of Biological Chemistry 278, 44009-44017 (2003).
Zhuo, Y., Hoyle, G.W., Zhang, J., Morris, G.F. and Lasky, J.A. A novel murine PDGF-D splicing variant results in significant differences in peptide expression and function. Biochemical and Biophysical Research Communications 308, 126-132 (2003).
G.F. Morris, A. Notwick, O. David, C. Fermin, A.R. Brody, and M. Friedman. Development of lung tumors in mutant p53-expressing mice after inhalation exposure to asbestos. Chest 125, Suppl. 5, 85S-86S (2004).
Shan, B. and Morris, G.F. Binding sequence-dependent regulation of the human proliferating cell nuclear antigen promoter by p53. Experimental Cell Research 305, 10-22 (2005).
Shan, B., Zhuo, Y., Chin, D., Morris, C.A., Morris, G.F. and Lasky, J.A. CDK9 is required for tumor necrosis factor-a stimulated MMP-9 expression in human lung adenocarcinoma cells. Journal of Biological Chemistry 280, 1103-1111 (2005).
Morris, G.F. and Brody, A.R. Molecular mechanisms of particle-induced lung disease. In: Environmental and Occupational Medicine. Fourth Edition. Rom, W.R. Ed. Little, Brown and Company, Boston, MA. (2006). nbsp;
Contact info: gmorris2@tulane.edu