COMPREHENSIVE GENE EXPRESSION PROFILING FOR TOXICOLOGY

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Studies in molecular toxicology, particularly those investigating chemical effects on gene expression, provide insight into the many mechanisms of toxicity and contribute to the assessment of potential health risks of chemicals in the environment. The objective of this proposal is to conduct and evaluate high-throughput gene expression assays for monitoring cellular responses to potentially hazardous (toxic) chemicals. in Phase I, the use of novel mass-labeled probes in conjunction with mass spectrometry was shown to be feasible for the accurate and sensitive detection of changes in the expression levels of selected sets of genes in mammalian cells. In Phase II, the assay will be implemented as a high- throughput, automated system capable of evaluating effects on multiple genes (10-25) in thousands of treated samples per day. Genes will be chosen for their association with toxicological endpoints that are of interest to potential corporate partners and to NIEHS. In addition to gene selection, the project will explore the extent to which analysis of dose response, time courses, and the use of different cell types provide comprehensive expression profiles. Analysis of these profiles may then be used for the comparison of novel against known compounds for predictive value and greater understanding of toxicological mechanisms. PROPOSED COMMERCIAL APPLICATION: GeneTrace intends to offer contract research programs for the analysis of chemical effects on gene expression using the technology described in this proposal. There is significant potential for commercial application if the assay is automated for high throughput and the cost per sample is sufficiently low. The information is important to toxicologists for classification of chemicals based on the induction of specific genes in a variety of cell types over a range of treatment concentrations and time. Because of the size of the modern chemical compound libraries, if the assay is efficient, then large-scale projects will be attractive to companies in the agricultural and chemical industries.