CELLULAR TARGETS FOR ABUSABLE DRUGS IN HUMAN PLACENTA

人胎盘中可滥用药物的细胞靶标

• 批准号: 2749122
• 负责人: VADIVEL GANAPATHY
• 金额: $ 25.31万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2749122
• 关键词: amphetamines; brush border membrane; choriocarcinoma; clinical research; cocaine; dopamine; embryo /fetus toxicology; female; human fetus tissue; human subject; laboratory rat; neurotransmitter transport; norepinephrine; nucleotides; placenta; preeclampsia; reproductive system pharmacology; serotonin; serotonin transporter; tissue /cell culture; trophoblast; vesicle /vacuole; women's health

DESCRIPTION: (Applicant's Abstract) Abuse of illicit drugs during pregnancy is currently a serious concern pertaining to women's health because of the deleterious effects these drugs have on the mother and on the fetus. The objective of the current project is to investigate the role of placenta in the pathogenesis of complications arising from abuse of cocaine and amphetamines during pregnancy and to establish that placenta is a direct target for these drugs. Human placenta expresses the serotonin transporter and the norepinephrine transporter, both of which are targets for cocaine and/or amphetamines. These transporters most likely function in the clearance of the vasoactive monoamines serotonin and norepinephrine from the intervillous space. Interference with their functions by cocaine and amphetamines would have had effects on the developing fetus. The current project will investigate the normal function, regulation, and ontogeny of these two transporters in the placenta. Studies will include detailed characterization of the interaction of cocaine and amphetamines with these two transporters. These studies will be done with isolated plasma membrane vesicles from the placenta and also with intact trophoblast cells and choriocarcinoma cells. The placental syncytiotrophoblast is a polarized cell and immunolocalization studies will be performed to determined whether or not the expression of the serotonin and norepinephrine transporters is polarized with regard to the maternal-facing brush border membrane and the fetal-facing basal membrane. Proposed studies will also delineate the differential role of hormones/cytokines in the modulation of these transporters using primary trophoblast cultures and choriocarcinoma cells. These studies will include analysis of hormone/cytokine-induced changes in the transport activity, transporter density and steady state levels of transporter-specific mRNAs. The specific signalling pathways mediating the hormone/cytokine effects will be identified and the involvement of transcriptional and translational processes and posttranslational modifications in the regulation will be delineated. Studies will also test the hypothesis that impaired function of one or both of these transporters is a pathogenic factor in preeclampsia, a condition which clinically resembles in many respects the complications arising from use of cocaine and amphetamines during pregnancy. The ontogenic development of the serotonin and norepinephrine transporters in placenta will be studied using the rat as the experimental model.

描述：（申请人摘要） 怀孕期间滥用非法药物目前是一个严重问题 由于这些药物具有有害作用，因此与女性健康有关 对母亲和胎儿都有影响。 当前项目的目标 目的是研究胎盘在并发症发病机制中的作用 因怀孕期间滥用可卡因和安非他明而引起 确定胎盘是这些药物的直接目标。 人胎盘 表达血清素转运蛋白和去甲肾上腺素转运蛋白，两者 其中目标是可卡因和/或安非他明。 这些转运者 最可能的功能是清除血管活性单胺血清素 和来自绒毛间隙的去甲肾上腺素。 干扰他们的 可卡因和安非他明的功能会对 发育中的胎儿。 当前项目将考察功能是否正常， 胎盘中这两种转运蛋白的调节和个体发育。 研究 将包括可卡因和可卡因相互作用的详细特征 安非他明与这两种转运蛋白。 这些研究将与 从胎盘中分离出质膜囊泡，并且具有完整的质膜囊泡 滋养层细胞和绒毛膜癌细胞。 胎盘 合体滋养层是一种极化细胞，免疫定位研究将 进行以确定血清素的表达是否 和去甲肾上腺素转运蛋白是极化的 面向母亲的刷状缘膜和面向胎儿的基底膜。 拟议的研究还将描述不同的作用 激素/细胞因子在这些转运蛋白的调节中使用初级 滋养层培养物和绒毛膜癌细胞。 这些研究将包括 分析激素/细胞因子诱导的转运活性变化， 转运蛋白密度和转运蛋白特异性 mRNA 的稳态水平。 介导激素/细胞因子效应的特定信号通路将 被识别以及转录和翻译的参与 法规中的过程和翻译后修改将 划定。 研究还将检验以下假设： 这些转运蛋白中的一种或两种是先兆子痫的致病因素， 临床上在许多方面与并发症相似的情况 因怀孕期间使用可卡因和安非他明而引起。 这 血清素和去甲肾上腺素转运蛋白的个体发育 将使用大鼠作为实验模型来研究胎盘。