Cell Signaling Research

Mossman Bio

Dr. Mossman's research group is studying the molecular mechanisms of chemical and physical carcinogenesis as well as and fibrotic lung disease caused by asbestos and other inhaled particulates (silica, glass and refractory ceramic fibers). She is also examining the relationship between active oxygen species and lung disease by these environmental pollutants. Epithelial cells, mesothelial cells and and fibroblasts of the respiratory tract in both cell and organ cultures are used to evaluate molecular, cytotoxic and proliferative changes after exposure to asbestos and other compounds. One of several projects is aimed at dissecting second messenger pathways including alterations in protein kinase cascades which may be involved in causing changes in gene expression. Another area of interest is determining the molecular mechanisms of increased cell proliferation and apoptosis by agents focusing on transcription and replication factors and activation of protooncogenes. This work is in collaboration with Dr. Heintz' and Janssen's laboratories. Studies in progress with Dr. Van Houten include the demonstration of oxidative damage by asbestos in RNA and DNA and experiments to determine the role of altered DNA repair in asbestos-induced cell injury and carcinogenesis using human mesothelial cells. Lastly, Dr. Mossman and coworkers are using in vitro systems of oxygen free radical generation to induce many of the changes observed in cells of the respiratory tract after addition of asbestos. Administration of scavengers of free radicals to both cells in culture and a rodent inhalation model of disease indicates that these agents can prevent asbestos-induced cytotoxicity and tissue damage.

The molecular regulation of antioxidant enzymes in lung cells in response to environmental agents may be important in lung defense. Increases in transcription and translation of protein of certain antioxidant enzymes, including heme oxygenase and manganese-containing superoxide dismutase are being explored as approaches to establishing biosensors of oxidant damage in cells lavaged from rodents and in human cells in vitro. Moreover, many of the hypotheses above are being explored using inhalation models of lung injury and transgenic mice deficient in antioxidant enzymes, receptor tyrosine kinases and protein kinases.