Gestational Age Variation in Human Placental Transport Mechanisms

描述（由申请人提供）：本研究项目拟对胎盘药物转移的关键成分进行研究，以提高我们对妊娠期间生理变化如何影响胎儿在妊娠不同阶段对药物的处置和暴露的理解。实现四个具体目标。研究的目的是：1)确定三种主要胎盘药物转运体：p -糖蛋白（P-gp）、血清素转运体（SERT）和去甲肾上腺素转运体（NET）的基因和蛋白表达的胎龄依赖性变化；2)利用胎盘膜囊泡制剂评估妊娠期胎盘转运蛋白的功能活性；3)确定妊娠早期和妊娠中期胎儿暴露于P-gp、SERT和NET底物的情况；4)建立跨胎龄药物胎盘转移的数学/统计模型。这些目标将解决公众和科学关注的关于怀孕期间药物暴露的潜在致畸和不良神经发育影响的主要问题。在了解胎盘药物运输的一些关键成分方面，特别是在妊娠早期和中期，人类数据很少。具有讽刺意味的是，这三个月是妊娠期发育最敏感的时期。我们将利用育龄妇女精神活性药物使用的高流行率，并利用我们独特的获得健康的妊娠1、2和3个月胎盘组织的途径，确定P-gp、SERT和NET在调节胎儿暴露于安非他明和艾司西酞普兰中的作用。这些精神药物通常被我们的临床人群服用。我们将比较所有三个妊娠期健康妇女的RNA和蛋白质表达研究结果（特异性目标#1），并检验与这些转运蛋白的功能活性高度相关的假设（特异性目标#2）。从我们的临床人群中，将收集在妊娠期间使用安非他明和艾司西酞普兰的妇女的配对母/胎儿样本，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性实验的结果将结合起来，建立数学模型，预测胎儿对相关药物和转运体的药物暴露（Specific Aim #4）。总的来说，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，这些特征可以预测怀孕前两个月胎儿药物暴露水平较低。这项转化性研究将促进对怀孕期间使用精神活性药物的胎儿风险作出更明智的决定。

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.