title: A morphology- and kinetics-based cascade for human neural cell high content screening.
abstract: The prospect of manipulating endogenous neural stem cells to replace damaged tissue and correct functional deficits represents a novel mechanism for treating a variety of central nervous system disorders. Using human neural precursor cultures and a variety of assays for studying stem cell behavior we have screened two libraries of commercially available compounds using an endpoint high content screening assay. We then performed detailed follow-up mechanistic studies on confirmed hits using endpoint and kinetics assays to characterize and differentiate the mechanisms of action of these compounds. The screening cascade employed successfully identified a number of active compounds with differing mechanisms of action. This approach shows how hits from a phenotypic screen can be prioritized and characterized by high content screening to identify potentially novel mechanisms and druggable targets to take forward into more conventional high-throughput screening approaches.
authors.affiliation: The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, UK. gillian_richards@merck.com
authors.forename: Gillian R
authors.initials: GR
authors.lastname: Richards
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Smith
authors.forename: Frances
authors.initials: F
authors.lastname: Parry
authors.forename: Amy
authors.initials: A
authors.lastname: Platts
authors.forename: Grace K Y
authors.initials: GK
authors.lastname: Chan
authors.forename: Mathew
authors.initials: M
authors.lastname: Leveridge
authors.forename: Julie E
authors.initials: JE
authors.lastname: Kerby
authors.forename: Peter B
authors.initials: PB
authors.lastname: Simpson
mesh_terms: D000818:Animals; D001681:Biological Assay / Q000379:methods*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007700:Kinetics; D016501:Neurites / Q000502:physiology / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology
chemical_list: D002118:Calcium