Mechanism of Fetal and Neonatal Handling of HIV Drugs

胎儿和新生儿处理 HIV 药物的机制

• 批准号: 7776954
• 负责人: SANJAY K NIGAM
• 金额: $ 32.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7776954
• 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; Physiological; 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

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（由申请方提供）：尽管大量感染HIV的孕妇和新生儿接受抗逆转录病毒药物的长期治疗，但对这些药物在子宫内和新生儿肾脏中的处理知之甚少。虽然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的担忧是合理的。这是儿科药理学中更普遍关注的问题的一部分，即由于对药物处理能力成熟的机制知之甚少，不适当的给药导致不必要的早产儿和新生儿药物毒性。关于用于治疗HIV的药物，来自PI小组和其他人的体外数据表明，有机阴离子转运蛋白（Oats）Oat 1和/或Oat 3是调节抗逆转录病毒处理的关键基因。PI的研究小组是第一个确定Oat 1以及一些相关基因的人，最近发表了第一个成年Oat 1和Oat 3基因敲除小鼠的数据，这些数据表明有机阴离子（OA）转运缺陷和药物处理改变。然而，某些OA化合物和药物在成年小鼠中的体内数据揭示了与主要从非洲爪蟾卵母细胞转运试验获得的体外数据的差异。此外，我们最近的发育研究，使用一种新的离体方法来分析OA处理，表明OA转运的燕麦非依赖性机制可能在子宫内和新生儿中很重要。根据大量的初步数据，在本修订申请中，我们假设早产儿和新生儿体内OA药物转运机制与成人不同。此外，我们假设，虽然燕麦1和燕麦3是关键的抗逆转录病毒转运蛋白在成人和可能在新生儿的设置，在子宫内额外的新型转运蛋白也有助于处理用于治疗艾滋病毒的抗逆转录病毒药物。这些路径需要定义。因此，我们的目标是解决以下问题：1）在新生野生型和基因敲除动物的肾脏中，Oat 1和Oat 3在抗逆转录病毒药物的净转运中的体内作用是什么？2)抗逆转录病毒药物在子宫内是否有其他转运途径？将采用遗传学、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。这些结果应该为药物在子宫内和新生儿环境中的处理机制（可能不同）提供关键见解，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。本申请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。