Alterations in serum microRNA in humans with alcohol use disorders impact cell proliferation and cell death pathways and predict structural and functional changes in brain.
Alterations in serum microRNA in humans with alcohol use disorders impact cell proliferation and cell death pathways and predict structural and functional changes in brain.
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DOI：
10.1186/s12868-015-0195-x
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发表时间：
2015-09-05
期刊：
影响因子：
2.4
通讯作者：
Middleton FA
中科院分区：
文献类型：
--
作者：
Ignacio C;Hicks SD;Burke P;Lewis L;Szombathyne-Meszaros Z;Middleton FA
目前缺乏可靠的、微创的生物标志物来预测酒精中毒引起的CNS损伤的程度。开发这种生物标志物可能有助于降低酒精使用障碍（AUDs）的患病率。细胞外microRNAs（miRNAs）可以作为神经元基因表达变化的信息分子指标。在这项研究中，我们对细胞外miRNA进行了全面分析，以确定诊断为DSM-IV AUDs的人类早期CNS损伤的可靠生物标志物。我们招募了一组相对年轻的20名AUD受试者和10名年龄匹配的对照。他们接受了全面的医学，神经心理学和神经影像学测试，然后比较了外周血血清中发现的miRNA水平。采用保守策略来鉴定候选生物标志物，使用两种独立的高通量方法定量miRNA：微阵列和下一代RNA测序。这提高了我们发现和验证相关miRNA的能力。我们的研究结果确定了几种在AUD受试者中与对照组相比具有显著且可重复的表达变化的miRNA。此外，候选miRNA生物标志物和各种医学，神经心理学和神经影像学参数之间的几个显着的关联被确定使用皮尔逊相关性和无偏分层聚类分析。一些最重要的候选生物标志物，如mir-92 b和mir-96，已经确定了在神经发育中的作用。使用两种不同的体内大鼠饮酒模型和两种不同的体外小鼠神经干细胞暴露模型进行miRNA表达的跨物种验证。系统水平分析显示，在所有这些数据集中观察到的最大变化具有显著程度的收敛性，特别是将细胞死亡、细胞增殖和细胞周期过程确定为最受影响的过程。虽然不一定是相同的分子，但这些通路中受影响的miRNA显然会影响共同的基因，如p53和TNF，它们是潜在的关键分子。最后，我们还通过量化这些生物标志物在15种不同组织类型中的水平来检查其潜在的组织来源，并表明其中几种在大脑中高度富集。总的来说，我们的研究结果表明，血清miRNA表达的变化可以直接与CNS结构和功能的改变，并可能通过对高度特异性的细胞通路的影响。本文的在线版本（doi：10.1186/s12868-015-0195-x）包含补充材料，可供授权用户使用。
There is currently a lack of reliable, minimally invasive biomarkers that could predict the extent of alcoholism-induced CNS damage. Developing such biomarkers may prove useful in reducing the prevalence of alcohol use disorders (AUDs). Extracellular microRNAs (miRNAs) can be informative molecular indicators of changes in neuronal gene expression. In this study, we performed a global analysis of extracellular miRNAs to identify robust biomarkers of early CNS damage in humans diagnosed with DSM-IV AUDs. We recruited a relatively young set of 20 AUD subjects and 10 age-matched controls. They were subjected to comprehensive medical, neuropsychological and neuroimaging tests, followed by comparison of miRNA levels found in peripheral blood serum. Employing a conservative strategy to identify candidate biomarkers, miRNAs were quantified using two independent high-throughput methods: microarray and next-generation RNA-sequencing. This improved our capacity to discover and validate relevant miRNAs. Our results identified several miRNAs with significant and reproducible expression changes in AUD subjects versus controls. Moreover, several significant associations between candidate miRNA biomarkers and various medical, neuropsychological and neuroimaging parameters were identified using Pearson correlation and unbiased hierarchical clustering analyses. Some of the top candidate biomarkers identified, such as mir-92b and mir-96 have established roles in neural development. Cross-species validation of miRNA expression was performed using two different in vivo rat drinking models and two different in vitro mouse neural stem cell exposure models. A systems level analysis revealed a remarkable degree of convergence in the top changes seen in all of these data sets, specifically identifying cell death, cell proliferation and cell cycle processes as most consistently affected. Though not necessarily the same molecules, the affected miRNAs within these pathways clearly influence common genes, such as p53 and TNF, which stand out as potential keystone molecules. Lastly, we also examined the potential tissue origins of these biomarkers by quantifying their levels in 15 different tissue types and show that several are highly-enriched in the brain. Collectively, our results suggest that serum miRNA expression changes can directly relate to alterations in CNS structure and function, and may do so through effects on highly specific cellular pathways. The online version of this article (doi:10.1186/s12868-015-0195-x) contains supplementary material, which is available to authorized users.