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首页> 外文期刊>BMC Genomics >Identification of placental nutrient transporters associated with intrauterine growth restriction and pre-eclampsia
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Identification of placental nutrient transporters associated with intrauterine growth restriction and pre-eclampsia

机译：鉴定与子宫内生长受限和先兆子痫相关的胎盘营养转运蛋白

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Gestational disorders such as intrauterine growth restriction (IUGR) and pre-eclampsia (PE) are main causes of poor perinatal outcomes worldwide. Both diseases are related with impaired materno-fetal nutrient transfer, but the crucial transport mechanisms underlying IUGR and PE are not fully elucidated. In this study, we aimed to identify membrane transporters highly associated with transplacental nutrient deficiencies in IUGR/PE. In silico analyses on the identification of differentially expressed nutrient transporters were conducted using seven eligible microarray datasets (from Gene Expression Omnibus), encompassing control and IUGR/PE placental samples. Thereby 46 out of 434 genes were identified as potentially interesting targets. They are involved in the fetal provision with amino acids, carbohydrates, lipids, vitamins and microelements. Targets of interest were clustered into a substrate-specific interaction network by using Search Tool for the Retrieval of Interacting Genes. The subsequent wet-lab validation was performed using quantitative RT-PCR on placentas from clinically well-characterized IUGR/PE patients (IUGR, n?=?8; PE, n?=?5; PE+IUGR, n?=?10) and controls (term, n?=?13; preterm, n?=?7), followed by 2D-hierarchical heatmap generation. Statistical evaluation using Kruskal-Wallis tests was then applied to detect significantly different expression patterns, while scatter plot analysis indicated which transporters were predominantly influenced by IUGR or PE, or equally affected by both diseases. Identified by both methods, three overlapping targets, SLC7A7, SLC38A5 (amino acid transporters), and ABCA1 (cholesterol transporter), were further investigated at the protein level by western blotting. Protein analyses in total placental tissue lysates and membrane fractions isolated from disease and control placentas indicated an altered functional activity of those three nutrient transporters in IUGR/PE. Combining bioinformatic analysis, molecular biological experiments and mathematical diagramming, this study has demonstrated systematic alterations of nutrient transporter expressions in IUGR/PE. Among 46 initially targeted transporters, three significantly regulated genes were further investigated based on the severity and the disease specificity for IUGR and PE. Confirmed by mRNA and protein expression, the amino acid transporters SLC7A7 and SLC38A5 showed marked differences between controls and IUGR/PE and were regulated by both diseases. In contrast, ABCA1 may play an exclusive role in the development of PE.
机译：妊娠障碍，如子宫内生长受限（IUGR）和先兆子痫（PE）是全世界围产期预后不良的主要原因。两种疾病都与母胎营养传递受损有关，但是尚未充分阐明IUGR和PE的关键转运机制。在这项研究中，我们旨在鉴定与IUGR / PE中胎盘营养缺乏症高度相关的膜转运蛋白。使用七个合格的微阵列数据集（来自Gene Expression Omnibus）对计算机进行了差异表达营养转运蛋白鉴定的计算机分析，其中包括对照和IUGR / PE胎盘样品。因此，在434个基因中，有46个被鉴定为潜在的目标。他们参与胎儿提供氨基酸，碳水化合物，脂质，维生素和微量元素。通过使用检索相互作用基因的搜索工具，将感兴趣的目标聚集到特定于底物的相互作用网络中。随后的湿实验室验证是使用定量RT-PCR对临床特征明确的IUGR / PE患者的胎盘进行的（IUGR，n == 8; PE，n == 5; PE + IUGR，n == 10 ）和控件（term，n？=？13; preterm，n？=？7），然后生成2D分层热图。然后使用Kruskal-Wallis检验进行统计评估，以检测明显不同的表达模式，而散点图分析表明哪些转运蛋白主要受IUGR或PE影响，或同等受两种疾病影响。通过两种方法鉴定，通过蛋白质印迹进一步研究了三个重叠的靶标SLC7A7，SLC38A5（氨基酸转运蛋白）和ABCA1（胆固醇转运蛋白）。从疾病和对照胎盘中分离的总胎盘组织裂解物和膜部分中的蛋白质分析表明，IUGR / PE中这三种营养转运蛋白的功能活性发生了变化。结合生物信息学分析，分子生物学实验和数学图解，这项研究证明了IUGR / PE中营养转运蛋白表达的系统改变。在46种最初靶向的转运蛋白中，根据IUGR和PE的严重性和疾病特异性，进一步研究了3个受到显着调节的基因。由mRNA和蛋白质表达证实，氨基酸转运蛋白SLC7A7和SLC38A5在对照和IUGR / PE之间显示出明显的差异，并受两种疾病的调节。相比之下，ABCA1可能在PE的发展中发挥独特作用。

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