MOLECULAR TOXICOLOGY GENE EXPRESSION AND CELL DEATH

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DESCRIPTION: (Adapted from the Investigator's Abstract): Long term exposure to environmental and drug toxicants is a health risk to the human population. However, the investigator's ability to identify potential risks has outstripped their ability to quantify the risk. Some environmental diseases may occur due to subtle changes in gene expression. Thus, estimating the risk associated with human exposure requires measurement of responses during the time when gene expression is leading to cumulative damages. The long term goal of this proposal is to identify mechanisms by which toxicants change expression of genes underlying these pathologies. In particular the investigator will address the question, "Is the c-myc gene a target for toxicant induced gene expression and what are the consequences of c-myc activation by the toxicants?" Preliminary studies, in kidney epithelial cells suggest that c-myc is activated by toxicants including S-(1,2-dichlorovinyl)-L- cysteine (DCVC), a metabolite of the environmental contaminant and industrial solvent trichlorethylene, and that downstream targets genes are turned on as a result. Moreover, it appears that these effects may be regulated by interactions with MAX and MAD proteins, members of the same family of transcription factor proteins as myc. Because c-myc expression is known to mediate processes including cell death (apoptosis), toxicant induced changes in c-myc expression may contribute to damage in the kidney or other organs. Proposed studies will begin to identify the early molecular changes which may lead to long term health effects of chemical exposure. It is suggested that basic research will identify discrete gene targets for toxicant exposure. These targets may provide a means to bioassay early human exposure allowing early responses to be monitored in exposed populations. Thus, the long term goal of this application is to use molecular technology to understand the risk of human exposure to drugs and chemicals.