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Terrance J. Kavanagh, Ph.D.

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Email: tjkav@u.washington.edu


Our laboratory conducts research in the areas of in vitro toxicology, analytical cytology and transgenic mouse models with emphasis on free radical biology, immunotoxicology, genetic toxicology, nanotoxicology and aging. We have been funded by the NIEHS to investigate the role of glutathione synthesis in protecting tissues from toxic chemical insult. We have made transgenic mice that conditionally overexpress glutamate-cysteine ligase (GCL, the rate-limiting enzyme in the synthesis of GSH) in the liver, and "knock-out" mice that lack the GCL modifier subunit (Gclm null mice). These mice are being used to test the hypothesis that GCL activity and glutathione synthesis are important in defense against free radical injury caused by exposure to a number of toxicants. Other areas of active research include: understanding chemical-induced liver injury using toxicogenomics and metabolomics; the role of genetics in air pollution susceptibility; and the toxicology of materials used in the nanotechnology industry.

Our laboratory also participates in the Toxicogenomics Research Consortium, a program that involves many researchers around the country. We are using our GCL mice and other mouse models to investigate the effects of toxic exposures on global gene expression. These data will be used to evaluate the sources of variability in carrying out DNA microarray experiments, as well as identify gene expression biomarkers that are applicable to a number of toxic exposures and species, including humans.

A rapidly growing area of investigation is the interface between the fields of toxicology and aging research. One theory of aging posits a role for free radicals in causing aging associated loss in proliferative homeostasis (which results in cancer, atherosclerosis, cellular senescence and other dysfunctional changes). We are especially interested in the role of GLCL in individual susceptibility to free radical and toxicant-mediated injury. We are conducting studies to determine the effects of GCL overexpression on cellular susceptibility to toxicant-induced DNA, protein and lipid damage, cell signaling and apoptosis. We are also interested in the factors that regulate GCL expression in humans and rodents.

We have also been working with Drs. George Martin and Peter Rabinovitch (Department of Pathology) who has generated catalase transgenic mice. These animals are being assessed for a variety of endpoints including susceptibility to free radical induced DNA damage, mutagenesis, altered transmembrane signal transduction and other toxicological endpoints. We are assessing the effects of overexpression of catalase on other antioxidant enzymes, including glutathione peroxidase, glutathione reductase, GLCL, and superoxide dismutases. Working with Dr. Michael Rosenfeld (Nutritional Sciences program) we are investigating the role of GSH synthesis in atherosclerosis, with emphasis on the influence of GCL expression and activity on macrophage biology.

Working with Drs. Dan Luchtel, Joel Kaufman and Rosenfeld, we are investigating the effects of diesel exhaust and particulate matter on the development and stability of atherosclerotic lesions in mice. This project will also examine the effects of these exposures on oxidative injury and inflammatory responses in the lung. Other collaborations include the role of GSH synthesis in the toxicity of beryllium (with Drs. Faustman and Takaro), the role of GSH synthesis in colon cancer (with Drs. Rabinovitch and Potter), and the role of GSH synthesis in fibrotic lung diseases (Drs. Raghu and Aitken).

Dr. Kavanagh also directs the Center for Ecogenetics and Environmental Health Analytical Cytology Core. This facility houses a Meridian Instruments ACAS Laser Scanning Cytometer for quantitative fluorescence measurements on cells and tissues, and for confocal microscopy. The core also has flow cytometry and digital image analysis equipment that is available to CEEH investigators

Selected Relevant Publications