title: An Integrated Human/Murine Transcriptome and Pathway Approach To Identify Prenatal Treatments For Down Syndrome.
abstract: 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.
authors: Mother Infant Research Institute, Tufts Medical Center and the Floating Hospital for Children, Boston, MA, United States.
authors: Faycal
authors: F
authors: Guedj
authors: Center for Health Protection (GZB), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
authors: Jeroen LA
authors: JL
authors: Pennings
authors: Mother Infant Research Institute, Tufts Medical Center and the Floating Hospital for Children, Boston, MA, United States.
authors: Lauren J
authors: LJ
authors: Massingham
authors: Department of Computer Science, Tufts University, Medford, MA, United States.
authors: Heather C
authors: HC
authors: Wick
authors: Mother Infant Research Institute, Tufts Medical Center and the Floating Hospital for Children, Boston, MA, United States.
authors: Ashley E
authors: AE
authors: Siegel
authors: Department of Pathology, Women and Infants' Hospital, Providence, RI, United States.
authors: Umadevi
authors: U
authors: Tantravahi
authors: Mother Infant Research Institute, Tufts Medical Center and the Floating Hospital for Children, Boston, MA, United States.
authors: Diana W
authors: DW
authors: Bianchi
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004622:Embryo, Mammalian; D005260:Female; D005333:Fetus; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000494:pharmacology; D049490:Systems Biology / Q000379:methods; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D054852:Small Molecule Libraries; C118778:USP16 protein, human; C108062:TTC3 protein, human; D044767:Ubiquitin-Protein Ligases; D043222:Ubiquitin Thiolesterase