Gestational Age Variation in Human Placental Transport Mechanisms

描述(申请人提供)：这项研究项目提出了关于胎盘药物转移的关键成分的研究，可以提高我们对怀孕期间生理变化如何影响怀孕不同阶段的药物处置和胎儿暴露的理解。将实现四个具体目标。这些研究旨在1)确定三种主要胎盘药物转运体：P-糖蛋白(P-gp)、5-羟色胺转运体(SERT)和去甲肾上腺素转运体(NET)的基因和蛋白表达随胎龄的变化；2)使用胎盘膜囊制剂评估胎盘转运体的功能活性；3)确定妊娠早期和中期胎儿对P-gp、SERT和Net底物的暴露；4)建立胎盘药物跨孕期药物转移的数学/统计模型。这些目标将解决公众和科学关注的重大问题，即怀孕期间药物暴露的潜在致畸和不良神经发育影响。要了解胎盘药物转运的一些关键成分，特别是在妊娠早期和中期，人体数据很少。具有讽刺意味的是，这三个月是发育最敏感的妊娠期。我们将利用育龄妇女使用精神活性药物的高流行率，并利用我们独特的获得健康的1、2、3个月胎盘组织的途径来确定P-gp、SERT和Net在调节胎儿苯丙胺和艾司匹兰暴露中的作用。这些精神活性药物通常是我们的临床人群服用的。我们将比较所有三个三个月的健康女性的RNA和蛋白质表达研究的结果(特定目标1)，并检验与这些转运蛋白的功能活性高度相关的假设(特定目标2)。从我们的临床人群中，将在怀孕期间使用苯丙胺和艾司匹林的妇女收集配对的母婴样本，以评估对我们的模型底物的暴露(具体目标3)。最后，我们的表达研究和功能活动实验的结果将结合起来，开发预测胎儿接触感兴趣的药物和转运体的数学模型(特定目标#4)。总体而言，我们的项目将产生数据，以帮助临床医生在治疗类别中选择具有特定特征的药物，这些药物预测怀孕前两个月较低的胎儿药物暴露。这项翻译研究将促进关于怀孕期间使用精神活性药物的胎儿风险的更明智的决定。

DESCRIPTION (provided by applicant): This research project proposes studies on key components of placental drug transfer that can improve our understanding of how physiological changes during pregnancy influence the disposition and fetal exposure of drugs at different stages of gestation. Four Specific Aims will be achieved. Studies are designed to 1) define gestational age dependant changes in the gene and protein expression of three major placental drug transporters: P-glycoprotein (P-gp), the serotonin transporter (SERT) and the norepinephrine transporter (NET); 2) assess the functional activity of placental transporters across gestation using placental membrane vesicle preparations; 3) define first and early second trimester fetal exposure to P-gp, SERT and NET substrates; and 4) develop mathematical /statistical models of placental drug transfer for drugs across gestational age. These aims will address major issues of public and scientific concern regarding potential teratogenic and adverse neuro-developmental effects of drug exposure during pregnancy. There are sparse human data to understand some key components of placental drug transport, especially in the first and second trimesters. Ironically, these trimesters are the most developmentally sensitive periods of gestation. We will capitalize on the high prevalence of psychoactive drug use in women of childbearing age and utilize our unique access to healthy 1st, 2nd, and 3rd trimester placental tissue to define the role of P-gp, SERT, and NET in regulating fetal exposure to amphetamine and escitalopram. These psychoactive drugs are commonly taken by our clinical population. We will compare the results of RNA and protein expression studies from healthy women in all three trimesters (Specific Aim #1) and test the hypothesis that a high correlation will be found with functional activity of these transporters (Specific Aim #2). From our clinical population, paired maternal/fetal samples will be collected in women using amphetamines and escitalopram across gestation to assess exposure to our model substrates (Specific Aim #3). Finally, the results of our expression studies and functional activity experiments will be combined to develop mathematical models predicting fetal drug exposure to the drugs and transporters of interest (Specific Aim #4). Overall, our project will generate data to aid clinicians in choosing drugs within therapeutic categories possessing specific characteristics that predict lower fetal drug exposure during the first two trimesters of pregnancy. This translational research will promote more informed decisions regarding fetal risk from psychoactive drug use during pregnancy.