Gestational Age Variation in Human Placental Transport Mechanisms

人类胎盘转运机制的孕龄变化

• 批准号: 8265527
• 负责人: C Lindsay LINDSAY DEVANE
• 金额: $ 13.76万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 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 2012-08-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265527
• 关键词: ABCB1 gene; ABCG2 gene; Address; Age; Amphetamines; Applications Grants; Birth; Carrier Proteins; Characteristics; Chemicals; Childhood; Data; Development; Discipline of obstetrics; Drug Exposure; Drug Kinetics; Drug Transport; Drug usage; Escitalopram; Exposure to; Female of child bearing age; Fetal Tissues; Fetus; Future; Genes; Genetic; Genetic Polymorphism; Genotype; Gestational Age; Gynecology; Health; Healthcare; High Prevalence; Human; In Vitro; Individual; Ions; Knowledge; Life; Link; Longevity; Maternal Health; Maternal and Child Health; Measures; Membrane; Mental disorders; Methods; Modeling; Mothers; Multi-Drug Resistance; Neurosciences; Nutrient; Operative Surgical Procedures; P-Glycoprotein; P-Glycoproteins; Patients; Pattern; Perinatal Exposure; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phenotype; Physiological; Placenta; Plasma; Population; Pregnancy; Pregnant Women; Preparation; Principal Investigator; Proteins; Psychiatry; Psychotropic Drugs; Public Health; Relative (related person); Research; Role; Safety; Simulate; Staging; Testing; Tissues; Translational Research; Variant; Vesicle; Western Blotting; addiction; base; clinical practice; design; experience; fetal; fetal drug exposure; human ABCG2 protein; improved; in utero; innovation; insight; link protein; medically necessary care; noradrenaline transporter; normal aging; novel; patient population; pharmacokinetic model; placental membrane; pregnant; protein expression; prototype; research study; response; serotonin transporter; theories

DESCRIPTION (provided by applicant): Exposure to drugs is a lifelong experience that begins in utero. Across the lifespan, from birth to extreme old age, the normal gestational period of approximately 37 weeks is the least understood period of drug disposition. The exposure of pregnant women to psychoactive drugs, regarded as medically necessary to maintain maternal health for a variety of mental disorders, and the exposure to illegal drugs, are critical public health care issues. Drug exposure of the fetus during pregnancy can have life-long pharmacodynamic consequences. Multiple transporter proteins have been shown to be involved in the passage of ions, nutrients, drugs, and other chemicals across the placental membranes in a bi-directional fashion. There exists a paucity of data related to the function of placental drug transporters to inform clinical practice regarding the selection and use of drugs that are transporter substrates. This grant application proposes studies in obstetrical pharmacology from three highly experienced Co-Principal Investigators to improve our ability to guide the use of drugs during pregnancy. Three specific aims are proposed to substantially enhance our knowledge of the placenta across human gestation and improve our understanding of the role of major drug transporters in regulating fetal drug exposure. Accordingly, we have chosen five major transporters for study: the ABCB1 gene encoded multi-drug resistance protein or P-glycoprotein (P-gp); ABCC3 gene encoded multidrug resistance protein (MRP3); ABCG2 gene encoded Breast Cancer Resistance Protein (BCRP); SLC6A2 gene encoded norepinephrine transporter (NET); and SLC6A4 gene encoded serotonin transporter (SERT). Specific aim 1 will define gestational age dependant changes in protein expression and functional activity of each transporter. Specific Aim 2 will define 1st, early 2nd, and 3rd trimester exposure to substrates of these transporters. Specific Aim 3 will benefit from the insight gained from aims 1 and 2 in the development of a physiologically- based pharmacokinetic model to predict placental drug transfer and fetal drug exposure using patient-specific characteristics. The availability of health placental tissue for study, representing all three trimesters, allows a unique opportunity to conduct this innovative research. The results will be significant in providing highly relevant data for understanding how drugs pass from the mother to her fetus at different periods of human gestation. PUBLIC HEALTH RELEVANCE: This research study will add significantly to the understanding of maternal fetal passage of psychoactive medications in pregnant women across gestation. Results will aid clinicians in selecting those medications that preserve maternal health while having the minimum impact on the developing fetus. Improved treatment of mental illness in pregnancy will improve both maternal and child health.

描述（由申请人提供）：药物暴露是从子宫内开始的终身经历。在整个生命周期中，从出生到极端老年，大约37周的正常妊娠期是药物处置最不了解的时期。孕妇接触精神活性药物，这在医学上被认为是维持产妇健康以治疗各种精神疾病所必需的，而接触非法药物是关键的公共保健问题。妊娠期间胎儿的药物暴露可能会产生终生的药效学后果。多种转运蛋白已被证明参与离子、营养物质、药物和其他化学物质以双向方式穿过胎盘膜。胎盘药物转运蛋白功能相关数据缺乏，无法为临床实践提供关于转运蛋白底物药物选择和使用的信息。这项拨款申请提出了三个经验丰富的共同主要研究者的产科药理学研究，以提高我们指导怀孕期间使用药物的能力。提出了三个具体的目标，以大大提高我们的知识胎盘在整个人类妊娠，提高我们的理解的作用，主要药物转运蛋白在调节胎儿药物暴露。因此，我们选择了五种主要的转运蛋白进行研究：ABCB 1基因编码的多药耐药蛋白或P-糖蛋白（P-gp）; ABCC 3基因编码的多药耐药蛋白（MRP 3）; ABCG 2基因编码的乳腺癌耐药蛋白（BCRP）; SLC 6A 2基因编码的去甲肾上腺素转运蛋白（NET）; SLC 6A 4基因编码的5-羟色胺转运蛋白（SERT）。具体目标1将定义每种转运蛋白的蛋白质表达和功能活性的胎龄依赖性变化。具体目标2将定义妊娠早期、妊娠早期和妊娠晚期暴露于以下底物的情况： 这些运输机。具体目标3将受益于从目标1和2中获得的见解，即开发基于生理学的药代动力学模型，以使用患者特异性特征预测胎盘药物转移和胎儿药物暴露。代表所有三个妊娠期的健康胎盘组织可用于研究，这为开展这项创新研究提供了独特的机会。其结果将在提供高度相关的数据方面具有重要意义 以了解药物如何在人类妊娠的不同时期从母亲传递给胎儿。 公共卫生关系：这项研究将大大增加对精神药物在整个妊娠期孕妇的母体胎儿通道的理解。研究结果将有助于临床医生选择那些既能保护产妇健康，又能对发育中的胎儿产生最小影响的药物。改善对怀孕期间精神疾病的治疗将改善孕产妇和儿童的健康。