Expression-based drug screening of neural progenitor cells from individuals with schizophrenia.

Autor:	Readhead B; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.; Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.; ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, 85287-5001, USA., Hartley BJ; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA., Eastwood BJ; Eli Lilly and Company Ltd, Erl Wood Manor, Surrey, UK., Collier DA; Eli Lilly and Company Ltd, Erl Wood Manor, Surrey, UK.; Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK., Evans D; Eli Lilly and Company Ltd, Erl Wood Manor, Surrey, UK., Farias R; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA., He C; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA., Hoffman G; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA., Sklar P; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA., Dudley JT; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.; Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA., Schadt EE; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. eric.schadt@mssm.edu.; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. eric.schadt@mssm.edu.; Sema4, a Mount Sinai venture, Stamford, Connecticut, USA. eric.schadt@mssm.edu., Savić R; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. radoslav.savic@mssm.edu.; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. radoslav.savic@mssm.edu.; Sema4, a Mount Sinai venture, Stamford, Connecticut, USA. radoslav.savic@mssm.edu., Brennand KJ; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. kristen.brennand@mssm.edu.; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. kristen.brennand@mssm.edu.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. kristen.brennand@mssm.edu.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. kristen.brennand@mssm.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2018 Oct 24; Vol. 9 (1), pp. 4412. Date of Electronic Publication: 2018 Oct 24.
DOI:	10.1038/s41467-018-06515-4
Abstrakt:	A lack of biologically relevant screening models hinders the discovery of better treatments for schizophrenia (SZ) and other neuropsychiatric disorders. Here we compare the transcriptional responses of 8 commonly used cancer cell lines (CCLs) directly with that of human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells (NPCs) from 12 individuals with SZ and 12 controls across 135 drugs, generating 4320 unique drug-response transcriptional signatures. We identify those drugs that reverse post-mortem SZ-associated transcriptomic signatures, several of which also differentially regulate neuropsychiatric disease-associated genes in a cell type (hiPSC NPC vs. CCL) and/or a diagnosis (SZ vs. control)-dependent manner. Overall, we describe a proof-of-concept application of transcriptomic drug screening to hiPSC-based models, demonstrating that the drug-induced gene expression differences observed with patient-derived hiPSC NPCs are enriched for SZ biology, thereby revealing a major advantage of incorporating cell type and patient-specific platforms in drug discovery.
Databáze:	MEDLINE
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