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Gestational Age Variation in Human Placental Transport Mechanisms

人类胎盘转运机制的孕龄变化

基本信息

批准号：
8449069
负责人：
C Lindsay LINDSAY DEVANE
金额：
$ 54.79万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
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/8449069
关键词：
ABCB1 gene ABCG2 gene Address Age Amphetamines Applications Grants Carrier Proteins Categories Characteristics Childhood Clinical Data Development Discipline of obstetrics Drug Exposure Drug Kinetics Drug Transport Drug usage Escitalopram Exposure to Female of child bearing age Fetal Tissues Fetus First Pregnancy Trimester Future Gene Expression Genes Genetic Genetic Polymorphism Genetic Transcription Genotype Gestational Age Gynecology Health High Prevalence Human In Vitro Individual Link Maternal Health Maternal and Child Health Measures Membrane Mental disorders Methods Modeling Mothers Multi-Drug Resistance Neurosciences Operative Surgical Procedures P-Glycoprotein P-Glycoproteins Patients Pattern Perinatal Exposure Pharmaceutical Preparations Pharmacology Phenotype Physiological Plasma Population Pregnancy Pregnancy Trimesters Pregnant Women Preparation Principal Investigator Proteins Psychiatry Psychotropic Drugs Relative (related person)Research Design Research Project Grants Risk Role Safety Sampling Second Pregnancy Trimester Simulate Staging Statistical Models Testing Therapeutic Tissues Translational Research Variant Vesicle Western Blotting Woman addiction base design fetal fetal drug exposure human ABCG2 protein human data improved innovation interest link protein mathematical model noradrenaline transporter novel patient population pharmacokinetic model placental membrane pregnant protein expression prototype research study response serotonin transporter theories

项目摘要

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）：本研究项目提出了胎盘药物转移的关键成分研究，可以提高我们对妊娠期间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。研究设计为：1）确定三种主要胎盘药物转运蛋白：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）的基因和蛋白表达的胎龄依赖性变化; 2）使用胎盘膜囊泡制剂评估胎盘转运蛋白在整个妊娠期间的功能活性; 3）定义妊娠早期和妊娠中期早期胎儿暴露于P-gp、SERT和NET底物;和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重大问题，即怀孕期间药物暴露的潜在致畸性和不良神经发育影响。有稀疏的人类数据来了解胎盘药物转运的一些关键组成部分，特别是在第一和第二孕期。具有讽刺意味的是，这三个月是妊娠期最发育敏感的时期。我们将利用育龄妇女中精神活性药物使用的高流行率，并利用我们独特的健康第1、第2和第3孕期胎盘组织来确定P-gp、SERT和NET在调节胎儿暴露于苯丙胺和艾司西酞普兰中的作用。这些精神活性药物是我们临床人群常用的药物。我们将比较所有三个孕期的健康女性的RNA和蛋白质表达研究结果（具体目标#1），并检验以下假设：将发现这些转运蛋白的功能活性具有高度相关性（具体目标#2）。从我们的临床人群中，将在妊娠期使用安非他明和艾司西酞普兰的女性中采集配对的母体/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，以开发预测胎儿药物暴露于目标药物和转运蛋白的数学模型（具体目标#4）。总的来说，我们的项目将产生数据，以帮助临床医生选择具有特定特征的治疗类别中的药物，这些药物预测妊娠前两个月期间胎儿药物暴露较低。这项转化研究将促进对妊娠期间使用精神活性药物的胎儿风险做出更明智的决定。