SNPs in Handling of Small Pox Antivirals and Other Drugs

SNP 在处理天花抗病毒药物和其他药物中的作用

• 批准号: 7603027
• 负责人: SANJAY K NIGAM
• 金额: $ 32.96万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7603027
• 关键词: Activities of Daily Living; Address; Anions; Antihypertensive Agents; Antiviral Agents; Binding Sites; Biological Assay; Cells; Cephaloridine; Cephalosporins; Chemoprophylaxis; Cidofovir; Clinical; Code; Collaborations; Communities; Computer Simulation; Data; Diuretics; Drug Kinetics; Drug Transport; Epidemic; Ethnic group; Event; Family member; Functional RNA; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Human; In Vitro; Individual; Individual Differences; Institutes; Investigation; Kidney; Kidney Failure; Knock-out; Mediating; Medical; Methotrexate; Modeling; Morbidity - disease rate; Nephrotoxic; Non-Steroidal Anti-Inflammatory Agents; Nucleic Acid Regulatory Sequences; Organ Culture Techniques; Organic Anion Transporters; Pathway interactions; Patients; Penicillins; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Phylogenetic Analysis; Physiological; Play; Positioning Attribute; Predisposition; Prophylactic treatment; Proximal Kidney Tubules; Publishing; Renal tubule structure; Research Personnel; Role; Route; Sampling; Silicon Dioxide; Single Nucleotide Polymorphism; Site; Smallpox; Structural Models; System; Techniques; Testing; Toxic Environmental Substances; Toxic effect; Toxin; Transfection; Tubular formation; Variant; Work; Xenopus oocyte; adefovir; base; comparative; interest; molecular marker; nephrotoxicity; ochratoxin A; programs; promoter; research study; response; thiazide; transcription factor

At physiological pH, many drugs (eg. penicillins, NSAIDs, methotrexate, thiazides) exist as organic anions and are eliminated via the kidney proximal tubule through multispecific renal organic anion transporters (especially OAT1 and OAT3). Apart from their general relevance to renal drug elimination, OATs are of current interest because they mediate nephrotoxicity of the antivirals cidofovir and adefovir, drugs which could be used in the event of a smallpox epidemic. Due to their toxicity, treatment and prophylaxis of many individuals with these drugs (as might be required in an epidemic) is likely to result in significant morbidity. Here, we hypothesize that altered function and expression of OAT1 and OAT3 due to coding and noncodinq region SNPs are key determinants of individual variation in renal drug elimination and nephrotoxicitv from drugs like cidofovir. The Pi's lab is in an ideal position to address this question as it was the first to identify the prototypical member of this family (originally called NKT, later termed OAT1), as well as several other SLC22 family members, and the first to describe a knockout of an OAT (OAT3). As part of this REVISED proposal, we aim to: 1) identify human SNPs in OAT1 and OATS in ethnically diverse samples; 2) employ two independent computational approaches (structural modeling and phylogenetic footprinting) to prioritize SNPs in terms of likelihood of functional effects on drug transport and OAT gene expression; 3) analyze the effects of coding region SNPs in order of in silica priority on in vitro drug transport (eg. using Xenopus oocyte and COS-7 expression systems) and the effects of noncoding SNPs on OAT gene expression (eg.by performing transfections of promoter constructs). We provide evidence of our ability to do all these studies and also have well-established (published) collaborations with individuals who have particular expertise in techniques that will support the project. We have done our best to address all the concerns of the previous review. Considerable new preliminary data, including major refinements in the computational model, are presented. Since a large, healthy, phenotyped group of patients treated with nephrotoxic drugs like cidofovir does not exist, we argue that this computational strategy of prioritizing OAT SNPs, followed by in vitro analysis of function and expression, is a logical approach for understanding the impact of OAT1 and OAT3 polymorphisms on handling of drugs and their toxicity. Ultimately, this work should provide the basis of a useful strategy to diminish renal failure in humans treated with nephrotoxic drugs.

在生理pH值时，存在许多药物（例如青霉素，NSAID，甲氨蝶呤，噻嗪类）作为有机阴离子存在，并通过肾脏近端小管通过多特异性肾脏有机阴离子转运蛋白（尤其是OAT1和OAT1和OAT3）消除。除了与消除肾脏药物的一般相关性外，燕麦还具有目前的意义，因为它们介导了抗病毒药cidofovir和adefovir的肾毒性，这些药物可以在天花流行病中使用。 由于其毒性，许多患有这些药物的人的治疗和预防（在流行病中可能需要）可能导致明显的发病率。在这里，我们假设由于编码和非Codinq区域SNP引起的OAT1和OAT3的功能和表达改变是肾脏药物消除和肾毒性毒素中个体变化的关键决定因素。 PI的实验室是解决这个问题的理想位置，因为它是第一个识别该家族的原型成员（最初称为NKT，后来称为OAT1）的人，以及其他几个SLC22家庭成员，也是第一个描述燕麦的敲除（OAT3）。作为这项修订的建议的一部分，我们的目标是：1）确定OAT1中的人类SNP和种族多样的样本中的燕麦； 2）采用两种独立的计算方法（结构建模 和系统发育足迹）以功能影响对药物传输和燕麦基因表达的可能性来确定SNP的优先级； 3）分析二氧化硅优先级顺序的编码区域SNP对体外药物转运的影响（例如，使用Xenopus oocyte和cos-7表达系统）以及非编码SNP对燕麦基因表达的影响（例如，通过对启动子构建体进行转染）。我们提供了我们有能力进行所有这些研究的能力的证据，并与具有支持该项目的技术专业知识的个人建立了良好的（已发布）合作。我们已尽最大努力解决了先前评论的所有问题。介绍了大量新的初步数据，包括计算模型中的主要改进。由于不存在用肾毒性药物治疗的大型，健康，表型的患者，例如Cidofovir，我们认为这是 优先级燕麦SNP的计算策略，然后在功能和表达的体外分析中，是理解OAT1和OAT3多态性对药物处理及其毒性的影响的逻辑方法。 最终，这项工作应为减少用肾毒性药物治疗的人类肾衰竭的有用策略提供基础。