Impact of Pregnancy Disease on the Regulation of Placenta Drug Transport

妊娠疾病对胎盘药物转运调节的影响

• 批准号: 8984894
• 负责人: CLIFFORD W MASON
• 金额: $ 24.64万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-02 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8984894
• 关键词: ABCB1 gene; ABCG2 gene; Address; Affect; Antibiotic Therapy; Antibiotics; Attenuated; Azithromycin; Biological Assay; Blood Circulation; CCAAT-Enhancer-Binding Proteins; Carrier Proteins; Cells; Cerebral Palsy; Chronic lung disease; Ciprofloxacin; Clinical; Data; Development; Dinoprostone; Disease; Drug Delivery Systems; Drug Efflux; Drug Transport; Effectiveness; Elements; Enzyme-Linked Immunosorbent Assay; Erythromycin; Exhibits; Exposure to; Fetus; Future; Gene Expression; Goals; Homologous Gene; Human; Immunohistochemistry; In Vitro; Infant; Infection; Infection prevention; Infiltration; Inflammatory; Injury; JUN gene; Knockout Mice; Knowledge; Measures; Mediating; Mentors; Mentorship; Messenger RNA; Modeling; Molecular; Mothers; Mus; Neonatal; Neurologic; P-Glycoproteins; PTGS2 gene; Pathway interactions; Penicillins; Perinatal Exposure; Pharmaceutical Preparations; Phase; Placenta; Pregnancy; Pregnancy Outcome; Premature Birth; Production; Prostaglandin Receptor; Prostaglandins; Proteins; Regulation; Regulator Genes; Research; Research Activity; Research Proposals; Scientist; Sepsis; Severities; Signal Transduction; Small Interfering RNA; Staging; Substrate Specificity; Techniques; Testing; Time; Tissues; Training; Transcription Factor AP-1; Treatment Efficacy; Up-Regulation; Ureaplasma; Ureaplasma Infections; Western Blotting; Woman; Work; Xenobiotics; chromatin immunoprecipitation; cytokine; fetal; fetal drug exposure; fetal infection; improved; in vivo; inflammatory marker; inhibitor/antagonist; intraamniotic infection; mRNA Expression; macrophage; malignant breast neoplasm; microorganism; mortality; mouse model; multi drug transporter; neonatal morbidity; neonatal outcome; neutrophil; novel therapeutic intervention; overexpression; p65; pathogen; placental transfer; protein function; reproductive; respiratory; response; therapeutic target; transcription factor; uptake

SUMMARY The primary objective of this proposal is to facilitate my development into an independent research scientist. This objective will be accomplished through a combination of active mentorship, didactic training, enrichment activities, and research. 100% of my time is committed to research. The mentorship phase is well described by my mentors and includes weekly contact and formal course work. The core of my research focuses on the pathopharmacology of the maternal-placental-fetal unit. Intrauterine infection is a major threat to mother and fetus. It is associated with more than 50% of women who deliver prematurely and is implicated in fetal / neonatal neurological and respiratory damage. Antibiotics are the primary treatment for infections during pregnancy, but because of poor placental transfer, fetal concentrations achieved are subtherapeutic. How the placenta regulates the transfer of antibiotics to the fetus is unclear, as is the impact of infection on drug transport. My preliminary data indicate there is up- regulation of the drug efflux transporters, multidrug resistence protein 1 (MDR1) and breast cancer resistence protein (BCRP), in the placenta of women with infection and associated chorioamnionitis. MDR1 and BCRP induction at the placental barrier could result in altered fetal drug exposure due to their broad substrate specificity and high level of expression in human placenta. The progressive research proposal addresses three core question: First, how does intra-amniotic infection affect placental MDR1/Mdr1a/b and BCRP/Bcrp1 (Mdr1a/b, Bcrp1, murine homologs of human MDR1 and BCRP)? Second, how do changes in MDR1/Mdr1a/b and BCRP/Bcrp1 activity affect the placental transfer and efficacy of antibiotics? Third, can drug delivery be manipulated by inhibiting the pathways that regulate transporter expression? In Specific Aim 1, I test the hypothesis that infection alters placental Mdr1a/b and Bcrp1 using a relevant mouse model of Ureaplasma infection and quantifying placental transporter levels. In Specific Aim 2, I test the hypothesis that modulation of Mdr1a/b and Bcrp1 alters the fetal distribution and therapeutic efficacy of antibiotics by measuring fetal drug levels and neonatal outcomes in wild-type, Mdr1a/b-/- (knockout) mice, Bcrp1-/- (knock-out) mice, and infected (Ureaplasma) mice. In Specific Aim 3, I propose to inhibit several prostaglandin (PG) E2 cascade elements, using pharmacological inhibitors and siRNA to test the hypothesis that prostaglandin (PG) E2 differentially regulates placental MDR1/Mdr1a/b and BCRP/Bcrp1 expression. The results will help predict how pathophysiological responses to infection in pregnancy affect the placental transfer and therapeutic efficacy of antibiotics. By the completion of these studies, I will have greatly expanded the scope of knowledge in efflux transporter mechanisms relevant to pregnancy and achieved independence as a research scientist.

摘要 这项建议的主要目的是促进我发展成为一名独立的研究科学家。这 目标将通过积极的指导、教学培训、充实活动、 和研究。我100%的时间都致力于研究。我的导师们很好地描述了导师阶段 并包括每周联系和正式课程工作。我的研究的核心是病理药理学 母体-胎盘-胎儿单元。宫内感染是母婴的主要威胁。它与以下内容关联 超过50%的早产妇女与胎儿/新生儿的神经系统和呼吸系统有关 损坏。抗生素是妊娠期感染的主要治疗方法，但因为胎盘不好 转移，达到的胎儿浓度是亚治疗。胎盘如何调节抗生素的转移 目前尚不清楚胎儿情况，也不清楚感染对药物运输的影响。我的初步数据显示- 药物外排转运体、多药耐药蛋白1与乳腺癌耐药的调控 感染和相关绒毛膜羊膜炎患者胎盘中的蛋白质(BCRP)。MDR1和BCRP 胎盘屏障的诱导可能导致胎儿药物暴露的改变，因为它们具有广泛的底物特异性。 以及在人类胎盘中的高水平表达。 这项渐进式研究计划解决了三个核心问题：第一，羊水内感染如何影响 胎盘mdr1/mdr1a/b和bcrp1(mdr1a/b，bcrp1，人mdr1和bcrp1的小鼠同源物)？ 第二，mdr1/mdr1a/b和bcrp/bcrp1活性的变化如何影响胎盘移植和疗效 抗生素？第三，是否可以通过抑制调节转运蛋白表达的途径来操纵药物传递？ 在特定的目标1中，我使用相关的小鼠检验了感染改变胎盘mdr1a/b和bcrp1的假设 解脲支原体感染模型和胎盘转运蛋白水平的量化。在具体目标2中，我检验了假设 Mdr1a/b和Bcrp1的调节通过测量改变抗生素的胎儿分布和治疗效果 野生型mdr1a/b-/-(敲除)小鼠、Bcrp1-/-(敲除)小鼠的胎儿药物水平和新生儿结局 感染(解脲支原体)小鼠。在具体目标3中，我建议抑制几个前列腺素(PG)E2级联元件， 使用药物抑制剂和siRNA验证前列腺素(PG)E2差异调节的假说 胎盘组织中mdr1/mdr1a/b和bcrp/bcrp1的表达。研究结果将有助于预测病理生理学 妊娠期对感染的反应影响胎盘移植和抗生素的治疗效果。由 完成这些研究后，我将极大地扩展外排转运机制的知识范围 与怀孕有关，并作为一名研究科学家获得了独立。