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Mechanism of Fetal and Neonatal Handling of HIV Drugs

胎儿和新生儿处理 HIV 药物的机制

基本信息

批准号：
8207357
负责人：
SANJAY K NIGAM
金额：
$ 10.94万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8207357
关键词：
ABCC1 gene Accounting Acquired Immunodeficiency Syndrome Address Adult Affect Affinity Amniotic Fluid Anesthesia procedures Anions Anti-Retroviral Agents Antiviral Agents Biological Assay Biology Birth Candidate Disease Gene Cells Child Chronic Disease Cidofovir Clinical Management Coculture Techniques Collaborations Combined Modality Therapy Conflict (Psychology)Data Developed Countries Development Didanosine Dose Drug Combinations Drug Compounding Drug Kinetics Drug Prescriptions Drug Transport Drug toxicity Drug usage Embryo Equilibrium Exposure to Family Family member Fetus Figs - dietary Genes Genetic HIV HIV Infections HIV-1 Highly Active Antiretroviral Therapy Immune system In Vitro Infant Infection Investigation Joints Kidney Kinetics Knock-out Knockout Mice Laboratories Lamivudine Lead Letters Long-Term Effects Low Birth Weight Infant Mediating Mesenchyme Metabolic Methods Microarray Analysis Microinjections Micropuncture Molecular Cloning Multidrug Resistance-Associated Proteins Mus Natural regeneration Nature Neonatal Newborn Animals Newborn Infant Nucleoside Transporter Nucleosides Oats Oocytes Organic Anion Transporters Pathway interactions Patients Perinatal Exposure Pharmaceutical Preparations Pharmacodynamics Play Population Pregnancy Outcome Pregnant Women Premature Birth Premature Infant Prevention Prophylactic treatment Protease Inhibitor Publishing RNA Relative (related person)Renal clearance function Reporting Reverse Transcriptase Inhibitors Risk Role Slice Sorting - Cell Movement Source Specificity Spinal Cord Staging Stavudine System Time Tissues Toxic effect Tubular formation Vertical Disease Transmission Viral Load result Work Xenopus laevis Xenopus oocyte Zidovudine adefovir base basolateral membrane design drug mechanism embryo tissue expression cloning fetal glomerular filtration in utero in vitro Model in vitro testing in vivo insight knockout animal mature animal member mitochondrial dysfunction mutant neglect neonate nephrogenesis non-nucleoside reverse transcriptase inhibitors novel nucleotide analog pediatric pharmacology prevent prophylactic research study spatiotemporal tool transcriptomics translational study transmission process uptake

项目摘要

DESCRIPTION (provided by applicant): Despite the large number of pregnant women and neonates infected with HIV receiving long-term treatment with antiretroviral agents, little is understood about the handling of these drugs in utero and in the neonatal kidney. Although the drugs are generally considered to be relatively safe for the fetus and neonate over the short-term, there is justifiable concern over undetected toxicities and long-term effects. This is part of a more general concern in pediatric pharmacology that unnecessary preterm and neonatal drug toxicity results from inappropriate dosing due to poorly understood mechanisms of maturation of drug handling capacity. With respect to drugs used for the treatment of HIV, in vitro data from the PI's group and others indicates that organic anion transporters (Oats), Oat1 and/or Oat3, are the key genes regulating antiretroviral handling. The PI's group was the first to identify Oat1, as well as a number of related genes, and has recently published the first adult Oat1 and Oat3 knockout mice data, which demonstrate defective organic anion (OA) transport and altered drug handling. However, the in vivo data in adult mice for certain OA compounds and drugs has revealed differences with in vitro data obtained mainly from Xenopus oocyte transport assays. Moreover, our recent developmental studies, using a novel ex-vivo method to analyze OA handling, suggest that Oat- independent mechanisms of OA transport may be important in utero and in neonates. Drawing on considerable preliminary data, in this REVISED application, we hypothesize that the mechanisms of in vivo OA drug transport are different in preterm and neonatal compared to adults. Furthermore, we hypothesize that, while Oat1 and Oat3 are the key antiretroviral transporters in adults and probably in the neonatal setting, in utero additional novel transporters also contribute to the handling of antiretrovirals used to treat HIV. These pathways need to be defined. We therefore aim to address the following questions: 1) What are the in vivo roles of Oat1 and Oat3 in net transport of antiretrovirals in the kidneys of neonatal wildtype and knockout animals? 2) Are additional pathways for transport of antiretrovirals active in utero? A combination of genetic, in vivo physiological, microarray and expression cloning methods will be employed to approach these questions, leveraging the joint strengths of the PI's group in OAT biology and kidney development. The results should provide key insights into the (likely different) mechanisms of drug handling in the in utero as well as neonatal settings and set the stage for translational studies. We have addressed all the criticisms of the prior application, including translational issues (please see letters from collaborators) and also provide new preliminary data. Despite the large number of pregnant women and neonates infected with HIV receiving long-term treatment with antiretroviral agents, little is understood about the handling of these drugs in utero and in the neonatal kidney. This application attempts to address the basic scientific aspects of antiretroviral drug handling in the immature kidney.

描述（由申请人提供）：尽管大量感染艾滋病毒的孕妇和新生儿接受抗逆转录病毒药物的长期治疗，但人们对这些药物在子宫内和新生儿肾脏中的处理知之甚少。尽管这些药物通常被认为在短期内对胎儿和新生儿相对安全，但对未检测到的毒性和长期影响存在合理的担忧。这是儿科药理学中更普遍关注的一部分，即由于对药物处理能力成熟机制知之甚少，剂量不当会导致不必要的早产儿和新生儿药物毒性。关于用于治疗艾滋病毒的药物，PI 小组和其他人的体外数据表明，有机阴离子转运蛋白（燕麦）、Oat1 和/或 Oat3 是调节抗逆转录病毒处理的关键基因。该 PI 的团队是第一个鉴定出 Oat1 以及许多相关基因的团队，并且最近发表了第一个成年 Oat1 和 Oat3 敲除小鼠的数据，这些数据证明了有机阴离子 (OA) 运输的缺陷和药物处理的改变。然而，某些 OA 化合物和药物的成年小鼠体内数据与主要从非洲爪蟾卵母细胞转运测定获得的体外数据存在差异。此外，我们最近的发展研究使用一种新颖的离体方法来分析 OA 处理，表明 OA 运输的独立于燕麦的机制可能在子宫内和新生儿中很重要。在这份修订后的申请中，根据大量的初步数据，我们假设早产儿和新生儿的体内 OA 药物转运机制与成人不同。此外，我们假设，虽然 Oat1 和 Oat3 是成人以及可能在新生儿环境中的关键抗逆转录病毒转运蛋白，但在子宫内其他新型转运蛋白也有助于处理用于治疗 HIV 的抗逆转录病毒药物。这些途径需要被定义。因此，我们的目标是解决以下问题：1）Oat1和Oat3在新生野生型和基因敲除动物肾脏中抗逆转录病毒药物净转运中的体内作用是什么？ 2) 抗逆转录病毒药物的其他转运途径在子宫内是否活跃？将利用遗传学、体内生理学、微阵列和表达克隆方法的组合来解决这些问题，利用 PI 小组在 OAT 生物学和肾脏发育方面的联合优势。研究结果应提供对子宫内和新生儿环境中药物处理（可能不同）机制的关键见解，并为转化研究奠定基础。我们已经解决了先前申请的所有批评，包括翻译问题（请参阅合作者的来信），并提供了新的初步数据。尽管大量感染艾滋病毒的孕妇和新生儿接受抗逆转录病毒药物的长期治疗，但人们对这些药物在子宫内和新生儿肾脏中的处理知之甚少。该应用试图解决未成熟肾脏中抗逆转录病毒药物处理的基本科学问题。