An Integrated Human/Murine Transcriptome and Pathway Approach To Identify Prenatal Treatments For Down Syndrome.
An Integrated Human/Murine Transcriptome and Pathway Approach To Identify Prenatal Treatments For Down Syndrome.
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DOI：
10.1038/srep32353
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发表时间：
2016-09-02
影响因子：
4.6
通讯作者：
Bianchi DW
中科院分区：
文献类型：
--
作者：
Guedj F;Pennings JL;Massingham LJ;Wick HC;Siegel AE;Tantravahi U;Bianchi DW
唐氏综合征(DS)胎儿时期就开始出现解剖和脑功能异常。我们假设，新的产前治疗可以通过靶向信号通路来识别，这些信号通路在从患有DS的人胚胎和小鼠胚胎中获得的细胞类型/组织中持续受到干扰。我们分析了21三体胎儿、年龄和性别匹配的整倍体对照组以及来自Ts1Cje、Ts65Dn和Dp16小鼠的胚胎15.5天前脑的转录组数据。新的数据集与来自DS患者的其他公开可用的数据集进行了比较。我们使用了人类连接图谱(Cmap)数据库，并创建了一个小鼠适应图，以确定FDA批准的可以拯救受影响路径的药物。Usp16和TTC3在所有受影响的人类细胞和两个小鼠模型中表达失调。DS相关的通路异常要么是基因剂量特异性效应的结果，要么是激活了代偿机制的整体细胞应激反应的结果。Cmap分析确定了56个具有高预测分数的分子，以挽救这两个物种的异常基因表达。我们新的人/鼠系统生物学集成方法确定了常见的失调基因和途径。这有助于确定治疗分子的优先顺序，以进一步测试安全性和有效性。在对小鼠进行临床前产前治疗之前，对人类细胞的其他研究正在进行中。
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.
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