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）：该研究项目提出了有关胎盘药物转移的关键组成部分的研究，这些研究可以提高我们对怀孕期间生理变化的理解，影响妊娠不同阶段的药物的处置和胎儿暴露。将实现四个具体目标。研究设计为1）定义了三种主要胎盘转运蛋白的基因和蛋白质表达的胎龄变化：P-糖蛋白（P-GP），5-羟色胺转运蛋白（SERT）和去甲肾上腺素转运蛋白（NET）； 2）使用胎盘囊泡制剂评估胎盘转运蛋白在妊娠之间的功能活性； 3）定义第一和第二孕期胎儿暴露于P-gp，SERT和净底物； 4）开发用于妊娠年龄的药物转移胎盘药物转移的数学 /统计模型。这些目的将解决有关在怀孕期间药物暴露的潜在致致致造性和不良神经发展影响的公共和科学关注的主要问题。人类数据稀少，可以理解胎盘运输的一些关键组成部分，尤其是在第一和第二个三物种中。具有讽刺意味的是，这些三个孕剂是发育敏感的妊娠期最敏感的时期。我们将利用精神活性药物在生育年龄的妇女中的高流行率，并利用我们独特的获得健康的第一，第二和第三个三个月胎盘组织的机会来定义P-gp，SERT和NET在调节胎儿暴露于Amphetamine和Escitalopram方面的作用。这些精神活性药物通常由我们的临床人群服用。我们将比较所有三个三个孕妇中健康女性的RNA和蛋白质表达研究的结果（特定的目标＃1），并检验了这些转运蛋白功能活性将发现高相关性的假设（特定的目标＃2）。从我们的临床人群中，将在妊娠之间使用苯丙胺和依他丙诺希望的女性中收集成对的母体/胎儿样本，以评估对我们的模型底物的接触（特定目标＃3）。最后，我们的表达研究和功能活性实验的结果将合并，以开发数学模型，以预测胎儿药物暴露于感兴趣的药物和转运蛋白（特定目标＃4）。总体而言，我们的项目将生成数据，以帮助临床医生在具有特定特征的治疗类别中选择药物，以预测胎儿药物在妊娠的前两个妊娠中的暴露。这项翻译研究将促进有关怀孕期间精神活性药物使用胎儿风险的更明智的决定。