ANEUGEN SCREENING IN OPTIMIZED C. ELEGANS STRAINS

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Although aneuploidy is known to play a significant role in many human health problems such as birth defects and cancer, we know little the about the possible aneugenicity of many chemicals and drugs. This proposal is aimed at developing a rapid, economical aneugenicity assay in C. elegans strains optimized for toxicity testing. Our assay will take advantage of the worm's use of X chromosome nondisjunction to produce XO males. Using male-specific GFP expression, we should be able to assess nondisjunction frequencies rapidly and easily. We will first characterize the relationship between GFP expression and nondisjunction in our assay. We will then test 20 known aneugens to gauge the similarity between our C. elegans-based assay and mammalian tests. Finally, we will attempt to increase the sensitivity of the assay using permeabilizing agents, inhibitors of P-gp transporters, and mutations that affect feeding behavior and chromosome segregation. Because many of these modifications will increase the sensitivity of C. elegans to toxins other than antigens, we predict that our optimization strategies will facilitate the development of a variety of C. elegans-based toxicity assays. PROPOSED COMMERCIAL APPLICATIONS: The C. elegans-based aneugen assays proposed here will be commercialized through 1) application to very early stage drug development, 2) application to the redesign of drugs with aneugenic activities, and 3) use in surveying chemical portfolios for potential aneugenicity-based liability exposure by insurers. The development of C. elegans strains optimized for toxicity testing may have an even larger commercial impact in that we plan to use the optimization strategies studied here to develop a wide range of toxicity tests.