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Series GSE166229 Query DataSets for GSE166229
Status Public on May 01, 2021
Title Universal Toxicity Gene Signatures for Early Identification of Drug-induced Tissue Injuries in Rats
Organism Rattus norvegicus
Experiment type Expression profiling by array
Summary A new safety testing paradigm that relies on gene expression biomarker panels was developed that can easily and quickly identify dose-dependent drug-induced injuries across a number of different tissues in rats prior to drug candidate selection. The resource-sparing approach has yielded positive impact on early compound de-risking, enabling drug advancement in a cost-effective manner while reducing later probability of attrition. Here we describe the development, qualification, and implementation of gene expression signatures that diagnose tissue degeneration/necrosis for use in an early rat Safety Lead Optimization (SLO) tolerability study or other early exploratory rat study conducted to assess drug action. Microarray data were used to first identify approximately 400 differentially expressed genes that were discovered as being shared consistently across 4 prioritized tissues (liver, kidney, heart, and skeletal muscle), following injuries induced by known toxicants and so were termed ‘universal’.   Quantitative PCR on ~100 of those genes followed, and the approach was extended across 4 other tissues (pancreas, 5 sections of the gastrointestinal tract (GI), bladder, and testes) where acute toxicities are historically less common. The most consistent and robustly responding transcripts were selected, resulting in a final 22-gene set (16 universal genes and 6 tissue-specific genes) from which unique sets of 12 genes were chosen as optimal for each of 8 tissues. Mathematical algorithms were generated to convert each tissue's gene expression fold change values for the 12 genes to a single metric, scaled between 0 and 1, and a positive threshold set. For liver, kidney, heart, and skeletal muscle, this was established using a training set of 22 compounds and the performance determined by testing a set of approximately 100 additional rat studies resulting in approximately 90% sensitivity and 100% specificity. Similar performance was observed across a more limited set of 15 studies for pancreas, GI, bladder, and testes. Bundled together, we have incorporated these gene expression signature panels into a 4 day rat SLO toxicity study design, which provides a rapid objective assessment of more commonly seen compound liabilities, benchmarks non-toxic and toxic doses and exposures, and guides selection of lead candidates to reduce attrition without the necessity to perform time-consuming tissue and slide preparation, and expert microscopic histopathologic analyses, which can be reserved for advancing more optimized compounds at later development stages.
 
Overall design Compilation of multiple different studies (TT#'s) of various design in liver, kidney, skeletal muscle and heart as indicated in the metadata.
 
Contributor(s) Tanis KQ, Glaab WE, Holder DH, He YD, Bailey WJ, Gerhold DL, Beare C, Erdos Z, Lane P, Michna L, Muniapppa N, Laurence JW, Sina JF, Skopek TR, Sistare FD
Citation(s) 33837425
Submission date Feb 04, 2021
Last update date Aug 06, 2021
Contact name Keith Tanis
E-mail(s) keith_tanis@merck.com
Organization name Merck & Co, Inc
Street address 770 Sumnetown Pike
City West Point
ZIP/Postal code 19486
Country USA
 
Platforms (2)
GPL3631 Rosetta/Merck Rat 50k v2.1 Array 1 microarray
GPL15569 Rosetta/Merck Rat 4.0 A1 microarray
Samples (222)
GSM5172906 Heart Day 03 Allylamine control pool vs. Heart; Day 03; Allylamine 000mkd # 1126-005:1070
GSM5172907 Heart Day 03 Allylamine control pool vs. Heart; Day 03; Allylamine 000mkd # 1126-005:1071
GSM5172908 Heart Day 03 Allylamine control pool vs. Heart; Day 03; Allylamine 000mkd # 1126-005:1072
Relations
BioProject PRJNA714669

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE166229_RAW.tar 252.3 Mb (http)(custom) TAR (of TXT)
Processed data included within Sample table
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