MIRA-Regulation of drug metabolizing enzymes

我的研究计划的总体目标是提高疗效和减少药物治疗的毒性 通过识别导致药物反应个体间差异的机制。主要 这项工作的重点是基因组变异性的影响，特别是在细胞色素P450（CYP）肝 药物代谢酶基因。药物通过代谢酶的代谢是主要的消除途径 用于大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 药物治疗无效、不良事件和住院治疗。在最常见的互动中， 是药代动力学的相互作用，主要是通过β-内酰胺酶。有大量的文献 影响基因编码区的遗传变异，但这只占一小部分， 药代动力学变异;对非编码区的变异知之甚少。源自我们的 过去NIGMS的资助已经证明，miRNAs调控着p53基因，并且它们的调控 基因组的变异性改变了功能。这些研究主要集中在3 'UTR中的SNP， 几个基因。鉴于这些重点研究的成功，在未来五年，我们计划扩大 这些努力有助于更广泛地了解miRNA在调节肝脏药物中的作用， 新陈代谢.我们计划利用我们新的高通量检测方法来测试基因的功能影响， 在各种调控区域的变体，以确定调节药物代谢的功能性变体。 使用我们已完成的临床试验的现有生物样本和药代动力学数据，我们将确定 所述变体与体内人代谢活性的关联。遗传变异显示影响 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， 展示了从实验室到床边的完整程序。miRNAs的可变表达也有助于 药物代谢的个体间差异。我们最近的研究结果表明， 在人类肝脏发育过程中，肝脏miRNA的表达是非常重要的，但关于其调控机制却知之甚少。 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 鉴定控制正常和异常的调节因子网络的最新技术 肝脏miRNA表达模式。加上我的成功合作记录网络，我们 有能力进行这些研究;我们的团队已经证明了基因组学方面的专业知识， 药理学，生物信息学，具有发现机制和生物标志物以及验证 在临床试验中。我们希望这些研究的结果能够提高我们准确预测 各种药物的疗效和毒性，通过代谢酶。另外我们 发现导致肝脏基因功能变异的分子机制可能会 可以应用于各种基因和疾病。

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.