MIRA-Regulation of drug metabolizing enzymes

我的研究计划的总体目标是提高药物治疗的疗效并减少其毒性 通过确定导致药物反应个体间差异的机制。主 这项工作的重点是基因组变异的影响，特别是在细胞色素P450(CYP)肝脏 药物代谢酶基因。药物的CYP酶代谢是主要的消除途径 很大一部分临床使用的药物。基因-药物和药物-药物相互作用是导致 药物治疗的无效、不良事件和住院治疗。在最常见的交互中 是药代动力学相互作用，主要通过CYP酶。有大量的文献关于 影响CYP编码区的遗传变异，但这只占 药代动力学可变性；对非编码区的变异知之甚少。结果来自我们的 过去的NIGMS研究表明，miRNAs调控CYP基因，并且它们的调控 功能会因基因组的可变性而改变。这些研究主要集中在#年3‘UTRs中的SNPs 几个CyP基因。鉴于这些重点研究的成功，我们计划在未来五年扩大 这些努力为理解miRNAs在调节肝脏药物中的作用提供了更广泛的途径 新陈代谢。我们计划利用我们的新型高通量分析来测试基因对功能的影响 在各种调控区域的变异，以确定调节药物新陈代谢的功能变异。 使用现有的生物制剂和我们已完成的临床试验的药代动力学数据，我们将确定 变异体与体内人体代谢活动的关系。基因变异被证明会影响 临床活动将纳入我们正在进行的药物基因组学临床实施工作中， 演示完整的从长凳到床边的程序。MiRNAs的可变表达也有助于 药物代谢中的个体间变异性。我们最近的研究结果表明， 在人类肝脏发育过程中的肝脏miRNA，但对其调控机制知之甚少 控制这些miRNA表达模式的机制。为了阐明这些机制，我们将使用 最先进的技术来识别控制正常和异常的调控因素网络 肝脏miRNA的表达模式。连同我记录在案的成功合作网络，我们 都有很好的条件进行这些研究；我们的团队已经展示了基因组学方面的专业知识， 药理学，生物信息学，在发现机制和生物标记物和验证方面的记录 他们正在进行临床试验。我们预计这些研究的结果将提高我们准确预测 通过CYP酶代谢的各种药物的有效性和毒性。此外，我们的 导致肝脏基因功能变异的分子机制的发现可能会 可应用于多种基因和疾病。

The overall goal of my research program is to improve the efficacy and reduce the toxicity of drug therapies by identifying the mechanisms that contribute to the interindividual variability in drug response. The main focus of this effort is on the impact of genomic variability, particularly in the cytochrome P450 (CYP) hepatic drug metabolizing enzyme genes. Metabolism of drugs by the CYP enzymes is the primary elimination route for a large portion of clinically used drugs. Gene-drug and drug-drug interactions are a major cause of inefficacy, adverse events, and hospitalizations from drug therapies. Among the most common interactions are the pharmacokinetic interactions, primarily through the CYP enzymes. There is extensive literature on the effects genetic variants in the CYP coding regions, but this only accounts for a small portion of the pharmacokinetic variability; much less is known about variants in the non-coding regions. Results from our past NIGMS funding have demonstrated that miRNAs regulate the CYP genes and that their regulatory functions are altered by genomic variability. Those studies were focused primarily on SNPs in the 3'UTRs in a few CYP genes. Given the success of those focused studies, over the next five years, we plan to expand these efforts to a broader approach to understanding the role of miRNAs in regulating hepatic drug metabolism. We plan to utilize our novel high throughput assays that test the functional impact of genetic variants in a variety of regulatory regions to identify the functional variants that regulate drug metabolism. Using existing biospecimens and pharmacokinetic data from our completed clinical trials, we will determine the associations of the variants with the in vivo human metabolic activity. Genetic variants shown to impact clinical activity will be incorporated into our ongoing pharmacogenomics clinical implementation efforts, demonstrating the complete bench to bedside program. Variable expression of miRNAs also contributes to the interindividual variability in drug metabolism. Our recent results indicate that there are dramatic changes in hepatic miRNA during the development of the human liver, but little is known about the regulatory mechanisms that control those miRNA expression patterns. To elucidate those mechanisms, we will use state of the art technologies to identify the network of regulatory factors that control normal and aberrant hepatic miRNA expression patterns. Together with my network of documented successful collaborations, we are well equipped to undertake these studies; our team has demonstrated expertise in genomics, pharmacology, bioinformatics with a track record of discovering mechanisms and biomarkers and validating them in clinical trials. We expect the results of these studies to improve our ability to accurately predict the efficacy and toxicity of a variety of drugs that are metabolized through the CYP enzymes. In addition, our discoveries of the molecular mechanism that contribute to the variability in hepatic gene function are likely to have applications to a wide variety of genes and diseases.