Whole animal assays offer many advantages for high throughput screening (HTS). Animals provide an integrated system response to compounds generating more efficacious and translatable screening hits. The microscopic nematode C. elegans is a good candidate organism for HTS. We have recently reported the development of a highly novel automated assay of C. elegans in which we were the first to publish the utility of automated worm handing. We are applying this technology to a modest screen for compounds that enhance resistance to thermal stress and oxidative stress at the whole organism level. This screen was prompted by our discovery that aging can be slowed by feeding C. elegans with salen manganese compounds that exhibit catalytic superoxide dismutase and catalase activities. We now propose to develop our automated end-point survival assay to critically assess the C. elegans system for HTS. Our immediate aim is to determine the inherent limitations of the C. elegans system by making a study of heterogeneity of response, efficiency of drug delivery and robustness of end-point assays. We also propose a series of developments to our standard operating procedure that will tailor C. elegans for HTS. Our longer term goal is to undertake HTS for compounds that protect against oxidative stress, extend lifespan and translate into mammalian models of age-related diseases such as Alzheimer's and Parkinson's. ? ?
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