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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

基本信息

批准号：
8785163
负责人：
CLIFFORD W MASON
金额：
$ 24.9万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/8785163
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 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-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 malignant breast neoplasm microorganism mortality mouse model multi drug transporter neonatal morbidity neutrophil novel therapeutics p65 pathogen placental transfer protein function reproductive respiratory response therapeutic target transcription factor uptake

项目摘要

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.

总结这个建议的主要目的是促进我发展成为一个独立的研究科学家。这目标将通过积极的指导、教学培训、充实活动与研究我100%的时间都花在研究上。我的导师们很好地描述了导师阶段并包括每周的联系和正式的课程工作。我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。与其相关联超过50%的早产妇女与胎儿/新生儿神经和呼吸系统疾病有关，损害抗生素是妊娠期感染的主要治疗方法，但由于胎盘组织不良，转移时，达到的胎儿浓度低于治疗浓度。胎盘如何调节抗生素的转移，胎儿的情况尚不清楚，感染对药物转运的影响也不清楚。我的初步数据显示- 药物外排转运蛋白、多药耐药蛋白1（MDR 1）与乳腺癌耐药蛋白（BCRP），在感染和相关绒毛膜炎的妇女胎盘。mdr 1和BCRP 由于广泛的底物特异性，胎盘屏障的诱导可能导致胎儿药物暴露的改变并在人胎盘中高水平表达。该研究提出了三个核心问题：第一，羊膜内感染如何影响胎盘MDR 1/Mdr 1 a/B和BCRP/Bcrp 1（Mdr 1 a/B、Bcrp 1、人MDR 1和BCRP的鼠同系物）？其次，MDR 1/Mdr 1a/B和BCRP/Bcrp 1活性的变化如何影响胎盘转移和抗生素吗第三，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，我使用相关小鼠检验了感染改变胎盘Mdr 1a/B和Bcrp 1的假设脲原体感染模型和定量胎盘转运蛋白水平。在具体目标2中，我检验了假设 Mdr 1a/B和Bcrp 1的调节通过测量野生型、Mdr 1a/B-/-（基因敲除）小鼠、Bcrp 1-/-（基因敲除）小鼠和感染（脲原体）小鼠。在具体目标3中，我建议抑制几种前列腺素（PG）E2级联元件，使用药理学抑制剂和siRNA来检验前列腺素（PG）E2差异调节胎盘MDR 1/Mdr 1a/B和BCRP/Bcrp 1表达。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转移和抗生素的治疗效果。由完成这些研究后，我将大大扩展外排转运体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。