We propose a novel in vitro human tissue cell-based toxicology screening approach based on Flow Cytometry (FCM) that can quickly and inexpensively identify toxic drug candidates and has the potential to uncover the molecular basis of the observed toxic effect. The lower costs and throughput of cell-based toxicity screening of hundreds of primary human cell lines derived from different tissues would enable efficient toxicity testing of early-stage drug candidates. Novasite's existing flow cytometry-based single cell screening technology platform is uniquely positioned to develop this approach. We have develop automated sample input and output handling devices for Flow Cytometry (FCM) that enable rapid screening of multiple tissue-specific human cell lines. Multiparametric capabilities enable simultaneous detection of multiple toxic effects of drug candidates on human cells based on their mechanism of action. Our high speed FCM sorter enables fast and accurate sorting of toxic versus non-toxic cells from a population of cells belonging to the same type. The differential pattern of gene expression in toxic versus non-toxic cells enables the identification of the molecular targets responsible for the observed toxicity. The serotonin system has been implicated in a wide range of psychiatric conditions including depression, anxiety disorders, obsessive-compulsive disorder, psychosis, eating disorders and substance abuse and dependence. The multiplicity of serotonergic molecular targets and their widespread distribution throughout the human body renders serotonin physiology extremely complex, both centrally and peripherally, with a common presence of important side effects for serotonergic drugs. The serotonin system is thus an excellent test case to probe the power of our novel human tissue cell-based toxicity approach to identify not only such side effects, but also the molecular targets responsible for the unwanted effect, which would guide medicinal chemistry approaches to remove the undesirable activity of drug candidates.
Thesaurus Terms: biomedical equipment development, cytotoxicity, flow cytometry, technology /technique development, toxicant screening cell surface receptor, drug discovery /isolation, serotonin cell line
