Small-molecule chemical probes are widely used as research tools to study biological function and disease mechanisms (Strausberg and Schreiber, 2003). Indeed, a major new initiative of the NIH Roadmap project has been the establishment of Molecular Libraries Screening Center Networks (MLSCN) (http://mli.nih.gov/mlscn/index.php). The goals of these centers are to provide academic researchers access to small molecule compound libraries that can be screened using high throughput robotics. Whole-genome RNAi-based libaries are also being used to identify genes involved in a variety of cellular pathways (Ashrafi et al., 2003; Friedman and Perrimon, 2006). However, a major limitation for most researchers is that their biological assays are not compatible or optimized for HTS. This has restricted access for many investigators as the screening centers accept only those assays that are already miniaturized for a multi-well format and shown to produce a robust and reproducible readout that can be quantified with HTS devices. Some considerations important for the development and validation of HTS assays (http://mli.nih.gov/mlscn/index.php) are that the assays should: 1) Be easy to automate with steps such as centrifugation, filtration and extraction avoided; 2) Have demonstrated capability of working reproducibly in a 96-, 384-, or 1536-well plate format; 3) Have signal of sufficient intensity with a signal-to-background ratio of at least 5 and a coefficient of variation (CV) below 10%; and 4) Have a Z'-factor value in the range of 0.5-1.0. These statistical values take into account both the assay signal dynamic range and the data variation (Zhang et al., 1999). The purpose of Core 6 is to facilitate the development of such assays for NINDS qualifying investigators such that the assays are validated for HTS.
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