Computational modelling of placental amino acid transfer as an integrated system.
Computational modelling of placental amino acid transfer as an integrated system.
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DOI：
10.1016/j.bbamem.2016.03.028
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发表时间：
2016-07
期刊：
影响因子：
--
通讯作者：
Sengers BG
中科院分区：
文献类型：
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作者：
Panitchob N;Widdows KL;Crocker IP;Johnstone ED;Please CP;Sibley CP;Glazier JD;Lewis RM;Sengers BG
胎盘氨基酸转移对胎儿发育至关重要，其损害与胎儿发育不良有关。氨基酸转运是由一系列具有重叠底物特异性的特定质膜转运蛋白介导的。然而，目前还不完全清楚这些不同的转运蛋白是如何共同调节胎盘的净流量的。因此，这项研究的目的是开发一个新的计算模型来描述人胎盘氨基酸转移是如何作为一个完整的系统发挥作用的。从母亲到胎儿的氨基酸转移需要通过胎盘合体滋养层细胞的两个质膜运输，每个质膜包含不同的转运蛋白补充。隔室建模方法与基于载体的建模框架相结合，以表示每个质膜上单个累积、交换和促进类转运蛋白的动力学。该模型成功地捕捉到了经胎盘转移的主要特征。模拟结果清楚地表明，调节转运蛋白的活性和条件，如苯丙酮尿症，可以增加某些氨基酸的转移，但这是以减少其他氨基酸的转移为代价的，这对开发胎盘和其他运输上皮的临床治疗方案具有意义。首先，胎盘氨基酸转运的计算模型作为一个完整的系统，转运蛋白的活性增加并不意味着向胎儿的转移增加。增加某些氨基酸的转移可以减少其他氨基酸的转移。氨基酸的组成和浓度决定着转移到胎儿体内的能力。苯丙酮尿症的模型提示母体苯丙氨酸过多会产生抑制作用。
Placental amino acid transfer is essential for fetal development and its impairment is associated with poor fetal growth. Amino acid transfer is mediated by a broad array of specific plasma membrane transporters with overlapping substrate specificity. However, it is not fully understood how these different transporters work together to mediate net flux across the placenta. Therefore the aim of this study was to develop a new computational model to describe how human placental amino acid transfer functions as an integrated system. Amino acid transfer from mother to fetus requires transport across the two plasma membranes of the placental syncytiotrophoblast, each of which contains a distinct complement of transporter proteins. A compartmental modelling approach was combined with a carrier based modelling framework to represent the kinetics of the individual accumulative, exchange and facilitative classes of transporters on each plasma membrane. The model successfully captured the principal features of transplacental transfer. Modelling results clearly demonstrate how modulating transporter activity and conditions such as phenylketonuria, can increase the transfer of certain groups of amino acids, but that this comes at the cost of decreasing the transfer of others, which has implications for developing clinical treatment options in the placenta and other transporting epithelia. First computational model of placental amino acid transfer as an integrated system Increased activity of a transporter does not mean increased transfer to the fetus. Increasing transfer of certain amino acids can reduce the transfer of others. Amino acid composition as well as concentration determines transfer to the fetus. Modelling of phenylketonuria suggests inhibition by excess maternal phenylalanine.