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: 8242507
• 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/8242507
• 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. PUBLIC HEALTH RELEVANCE: These studies will increase our knowledge of transporter mechanisms relevant to pregnancy and help predict how pathophysiological responses to infection in preterm pregnancy will affect the placental transfer and therapeutic efficacy of drugs.

描述（由申请人提供）：本提案的主要目标是促进我发展成为一名独立研究科学家。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%的时间都花在研究上。我的导师对指导阶段进行了详细的描述，包括每周的联系和正式的课程工作。我的研究核心集中在母体-胎盘-胎儿单位的病理药理学。宫内感染是母婴的主要威胁。它与超过50%的早产妇女有关，并与胎儿/新生儿神经和呼吸系统损伤有关。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，胎儿达到的浓度低于治疗浓度。胎盘如何调节抗生素向胎儿的转运尚不清楚，感染对药物转运的影响也不清楚。我的初步数据表明，在感染和相关绒毛膜炎的女性胎盘中，药物外排转运蛋白、多药耐药蛋白1（MDR 1）和乳腺癌耐药蛋白（BCRP）上调。由于MDR1和BCRP在人胎盘中具有广泛的底物特异性和高水平表达，因此在胎盘屏障诱导MDR1和BCRP可能导致胎仔药物暴露量改变。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/Bcrp 1（Mdr1a/B，Bcrp 1，人类MDR1和BCRP的鼠同源物）？其次，MDR1/Mdr1a/B和BCRP/Bcrp1活性的变化如何影响胎盘转移和抗生素的疗效？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递送？在具体目标1中，我使用脲原体感染的相关小鼠模型和定量胎盘转运蛋白水平来检验感染改变胎盘Mdr1a/B和Bcrp 1的假设。在具体目标2中，我通过测量野生型、Mdr1a/B-/-（敲除）小鼠、Bcrp 1-/-（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，检验了Mdr1a/B和Bcrp 1的调节改变抗生素的胎儿分布和疗效的假设。在具体目标3中，我建议使用药理学抑制剂和siRNA来抑制几种前列腺素（PG）E2级联元件，以检验前列腺素（PG）E2差异调节胎盘MDR 1/Mdr1a/B和BCRP/Bcrp 1表达的假设。这些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转移和抗生素的治疗效果。通过这些研究的完成，我将极大地扩展与妊娠相关的外排转运机制的知识范围，并实现作为研究科学家的独立性。 公共卫生相关性：这些研究将增加我们对妊娠相关转运机制的了解，并有助于预测早产感染的病理生理反应将如何影响胎盘转运和药物治疗效果。