An Integrated Human/Murine Transcriptome and Pathway Approach To Identify Prenatal Treatments For Down Syndrome
| Autor: | Diana W. Bianchi, Umadevi Tantravahi, Lauren J. Massingham, Ashley E. Siegel, Heather C. Wick, Faycal Guedj, Jeroen L. A. Pennings |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Down syndrome Systems biology Ubiquitin-Protein Ligases Gene Dosage Mice Transgenic Biology Bioinformatics Gene dosage Article Transcriptome Small Molecule Libraries 03 medical and health sciences Mice 0302 clinical medicine Fetus Cell Line Tumor medicine Animals Humans Gene Regulatory Networks Gene Genetics Multidisciplinary Systems Biology Brain Gene Expression Regulation Developmental medicine.disease Embryo Mammalian Embryonic stem cell 3. Good health Disease Models Animal 030104 developmental biology Female Down Syndrome Trisomy Ubiquitin Thiolesterase 030217 neurology & neurosurgery Metabolic Networks and Pathways Signal Transduction |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | Anatomical and functional brain abnormalities begin during fetal life in Down syndrome (DS). We hypothesize that novel prenatal treatments can be identified by targeting signaling pathways that are consistently perturbed in cell types/tissues obtained from human fetuses with DS and mouse embryos. We analyzed transcriptome data from fetuses with trisomy 21, age and sex-matched euploid controls and embryonic day 15.5 forebrains from Ts1Cje, Ts65Dn and Dp16 mice. The new datasets were compared to other publicly available datasets from humans with DS. We used the human Connectivity Map (CMap) database and created a murine adaptation to identify FDA-approved drugs that can rescue affected pathways. USP16 and TTC3 were dysregulated in all affected human cells and two mouse models. DS-associated pathway abnormalities were either the result of gene dosage specific effects or the consequence of a global cell stress response with activation of compensatory mechanisms. CMap analyses identified 56 molecules with high predictive scores to rescue abnormal gene expression in both species. Our novel integrated human/murine systems biology approach identified commonly dysregulated genes and pathways. This can help to prioritize therapeutic molecules on which to further test safety and efficacy. Additional studies in human cells are ongoing prior to pre-clinical prenatal treatment in mice. |
| Databáze: | OpenAIRE |
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