Gestational Age Variation in Human Placental Transport Mechanisms

人类胎盘转运机制的孕龄变化

• 批准号: 8600751
• 负责人: C Lindsay LINDSAY DEVANE
• 金额: $ 45.05万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8600751
• 关键词: Gestational; Age; Variation; Human; Placental

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.

描述（由申请人提供）：该研究项目提出对胎盘药物转移的关键组成部分的研究，可以提高我们对怀孕期间的生理变化如何影响妊娠不同阶段药物的处置和胎儿暴露的理解。将实现四个具体目标。研究旨在 1) 定义三种主要胎盘药物转运蛋白的基因和蛋白表达的孕龄依赖性变化：P-糖蛋白 (P-gp)、血清素转运蛋白 (SERT) 和去甲肾上腺素转运蛋白 (NET)； 2) 使用胎盘膜囊泡制剂评估整个妊娠期胎盘转运蛋白的功能活性； 3) 定义妊娠早期和中期妊娠早期胎儿对 P-gp、SERT 和 NET 底物的暴露； 4) 开发跨胎龄药物的胎盘药物转移的数学/统计模型。这些目标将解决公众和科学界关注的有关怀孕期间药物暴露潜在致畸和不良神经发育影响的主要问题。人类数据很少，无法了解胎盘药物转运的一些关键组成部分，特别是在妊娠早期和中期。讽刺的是，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中精神药物使用的高流行性，并利用我们独特的健康第一、第二和第三个月胎盘组织的途径来确定 P-gp、SERT 和 NET 在调节胎儿接触安非他明和艾司西酞普兰。这些精神活性药物通常被我们的临床人群服用。我们将比较健康女性在所有三个三个月期的 RNA 和蛋白质表达研究结果（具体目标 #1），并检验这些转运蛋白与功能活性存在高度相关性的假设（具体目标 #2）。从我们的临床人群中，将在妊娠期间使用安非他明和艾司西酞普兰的女性中收集配对的母体/胎儿样本，以评估对我们的模型底物的暴露情况（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数学模型，预测胎儿药物暴露于感兴趣的药物和转运蛋白（具体目标#4）。总体而言，我们的项目将生成数据，帮助临床医生在具有特定特征的治疗类别中选择药物，这些特征可预测妊娠前两个三个月胎儿药物暴露量较低。这项转化研究将促进就怀孕期间使用精神活性药物对胎儿造成的风险作出更明智的决定。