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: 8403949
• 负责人: CLIFFORD W MASON
• 金额: $ 12.85万
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403949
• 关键词: ABCB1 gene; ABCG2 gene; Address; Affect; Antibiotic Therapy; Antibiotics; Attenuated; Azithromycin; Biological Assay; Blood Circulation; Carrier Proteins; Cells; Cerebral Palsy; Chronic lung disease; Ciprofloxacin; Clinical; Commit; 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 of amniotic sac and membranes; Infection prevention; Infiltration; Inflammatory; Injury; JUN gene; Knockout Mice; Knowledge; Measures; Mediating; Mentors; Mentorship; Messenger RNA; Modeling; Molecular; Mothers; Mus; Neonatal; Neurologic; Outcome; P-Glycoprotein; 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; human ABCG2 protein; improved; in vivo; inflammatory marker; inhibitor/antagonist; intraamniotic infection; mRNA Expression; macrophage; microorganism; mortality; mouse model; neonatal morbidity; neutrophil; novel therapeutics; p65; pathogen; placental transfer; protein function; reproductive; respiratory; response; therapeutic target; transcription factor; uptake

DESCRIPTION (provided by applicant): 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 resistance protein 1 (MDR1) and breast cancer resistance 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 questions: 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.

描述（由申请人提供）：本提案的主要目的是促进我发展成为一名独立的研究科学家。这一目标将通过积极的指导、教学培训、丰富活动和研究相结合来实现。我100%的时间都用在研究上了。我的导师很好地描述了师友阶段，包括每周联系和正式的课程作业。我的研究核心集中在母体-胎盘-胎儿单位的病理药理学。宫内感染是对母亲和胎儿的主要威胁。它与50%以上的早产妇女有关，并与胎儿/新生儿神经和呼吸损伤有关。抗生素是妊娠期感染的主要治疗方法，但由于胎盘转移不良，胎儿浓度达到治疗效果。胎盘如何调节抗生素向胎儿的转移尚不清楚，感染对药物运输的影响也不清楚。我的初步数据表明，感染和相关的绒毛膜羊膜炎妇女的胎盘中存在药物外排转运蛋白，多药耐药蛋白1 （MDR1）和乳腺癌耐药蛋白（BCRP）的上调。由于MDR1和BCRP在人胎盘中的广泛底物特异性和高水平表达，在胎盘屏障处的诱导可能导致胎儿药物暴露的改变。该研究计划解决了三个核心问题：首先，羊膜内感染如何影响胎盘MDR1/Mdr1a/b和BCRP/Bcrp1 （Mdr1a/b, Bcrp1，人类MDR1和BCRP的小鼠同源物）？其次，MDR1/Mdr1a/b和BCRP/Bcrp1活性的变化如何影响胎盘移植和抗生素的疗效？第三，能否通过抑制调节转运蛋白表达的途径来操纵药物的传递？在Specific Aim 1中，我使用脲原体感染的相关小鼠模型和量化胎盘转运蛋白水平，验证了感染改变胎盘Mdr1a/b和Bcrp1的假设。在Specific Aim 2中，我通过测量野生型、Mdr1a/b-/-（敲除）小鼠、Bcrp1-/-（敲除）小鼠和感染（脲原体）小鼠的胎儿药物水平和新生儿结局，验证了Mdr1a/b和Bcrp1的调节改变抗生素的胎儿分布和治疗效果的假设。在Specific Aim 3中，我提出抑制几个前列腺素（PG） E2级联元件，使用药物抑制剂和siRNA来验证前列腺素（PG） E2差异调节胎盘MDR1/Mdr1a/b和BCRP/Bcrp1表达的假设。该结果将有助于预测妊娠期感染的病理生理反应如何影响胎盘移植和抗生素的治疗效果。通过这些研究的完成，我将大大扩展与妊娠相关的外排转运体机制的知识范围，并获得作为研究科学家的独立性。