Regulation of drug metabolizing enzymes by miRNAs

miRNA 对药物代谢酶的调节

• 批准号: 7943130
• 负责人: Todd C. Skaar
• 金额: $ 40.75万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7943130
• 关键词: Address; Adult; Affect; Algorithms; Bioinformatics; Biological; Biological Assay; Boxing; CYP2D6 gene; Cessation of life; Child; Clinical; Clinical Pharmacology; Computer Simulation; Consent; Cytochrome P450; Data; Development; Developmental Gene; Dose; Drug Exposure; Drug Interactions; Drug Kinetics; Drug Regulations; Economics; Enzymes; Foundations; Functional RNA; Future; Gene Expression; Gene Proteins; Genetic Variation; Goals; Health Care Costs; Hepatic; Hospitalization; Human; In Vitro; Individual; Infant; Label; Lead; Liver; Metabolism; MicroRNAs; Molecular; Molecular Biology; Neonatal; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Positioning Attribute; Reaction; Receptor Signaling; Regulation; Research; Research Personnel; Role; Safety; Sampling; Skiing; Staging; Testing; Therapeutic; Time; Tissue Sample; Tissue-Specific Gene Expression; Tissues; Translating; Variant; Work; base; cost; drug efficacy; drug metabolism; fetal; improved; innovation; metabolic abnormality assessment; protein expression; public health relevance; receptor; response

DESCRIPTION (provided by applicant): Variable drug disposition is a well recognized cause of altered drug efficacy and impaired safety. While some of the causes of this variability are known, much of it is still unexplained; consequently, many of the adverse drug reactions and drug efficacy determinants are still unpredictable. Since drug metabolism is a primary determinant of pharmacokinetics and most clinically serious drug-interactions are the result of alterations in drug metabolism, we wish to evaluate additional mechanisms that regulate the expression of the drug metabolizing enzymes. One important factor that contributes to variable drug metabolism is developmental change in the expression of the cytochrome P450 (CYP450) enzymes; this is a particularly important factor to consider in infants and young children. The central hypothesis of this proposal is that endogenous microRNAs (miRNAs) regulate developmental changes in the expression of key drug metabolizing enzymes, and thereby, altering drug exposure. Endogenous miRNAs are small non-coding RNAs that regulate gene and protein expression; this includes the important role of developmental regulation of tissue-specific gene expression. Our hypothesis is based on our preliminary data that suggest that miRNAs also regulate key CYP drug metabolizing enzymes. Our long-range goal is to improve the efficacy and safety of therapeutic drugs by better understanding and then reducing interindividual pharmacokinetic variability. We will test our hypotheses through the following specific aims: 1) To identify miRNAs that are predicted to control hepatic drug metabolism. The results of this bioinformatic effort will have broad biological relevance to the understanding of this important class of enzymes. 2) To determine the changes in global miRNA expression patterns that occur during the development of hepatic CYP450 activity. These studies will focus on the human fetal, neonatal/pediatric, and adult periods. 3) To identify miRNA expression patterns that are associated with the documented developmental changes in a single, but critical drug-metabolizing enzyme: CYP2D6. 4) To use in vitro miRNA bioassays to functionally test the predicted miRNA regulation of CYP2D6 expression. This project is highly innovative because it addresses the developmental variation seen in drug metabolism using new molecular mechanisms inherent in control by miRNA. These efforts may also have important implications for interindividual transporter, receptor, and signaling variability in children and adults. We have assembled a team of investigators that have well-recognized expertise in clinical pharmacology, molecular biology and bioinformatics. As part of this team, we have access to a wealth of appropriately consented clinical samples that will enable us to translate our findings directly into human studies. A better understanding of the developmental control mechanisms of the human hepatic CYP450 enzymes will likely improve our understanding of the developmental changes that occur in human drug metabolism. Ultimately, this should lead to improved therapeutic drug dosing strategies, particularly during critical times of developmental change. PUBLIC HEALTH RELEVANCE: We will be studying the underlying mechanisms that contribute to adverse drug reactions and poor drug efficacy. We will determine the role of small endogenous microRNAs in the regulation of liver drug metabolizing enzymes. These studies should help us better understand the interindividual variability in drug responses, and consequently improve drug therapies.

描述（由申请人提供）：药物处置可变是药物疗效改变和安全性受损的公认原因。虽然这种变异性的一些原因是已知的，但其中大部分仍然无法解释;因此，许多药物不良反应和药物疗效决定因素仍然是不可预测的。由于药物代谢是药代动力学的主要决定因素，并且大多数临床上严重的药物相互作用是药物代谢改变的结果，因此我们希望评估调节药物代谢酶表达的其他机制。导致药物代谢变化的一个重要因素是细胞色素P450（CYP 450）酶表达的发育变化;这是婴儿和幼儿需要考虑的一个特别重要的因素。该提议的中心假设是内源性microRNAs（miRNAs）调节关键药物代谢酶表达的发育变化，从而改变药物暴露。内源性miRNAs是一类调控基因和蛋白表达的小分子非编码RNA，在发育过程中对组织特异性基因表达具有重要调控作用。我们的假设是基于我们的初步数据，表明miRNA也调节关键的药物代谢酶。我们的长期目标是通过更好地理解和降低个体间药代动力学变异性来提高治疗药物的疗效和安全性。我们将通过以下具体目标来验证我们的假设：1）鉴定预测控制肝脏药物代谢的miRNA。这一生物信息学努力的结果将对理解这类重要的酶具有广泛的生物相关性。2)确定肝脏CYP 450活性发展过程中总体miRNA表达模式的变化。这些研究将重点关注人类胎儿、新生儿/儿童和成人期。3)确定与记录的单一但关键的药物代谢酶CYP 2D 6的发育变化相关的miRNA表达模式。4)使用体外miRNA生物测定法对预测的miRNA对CYP 2D 6表达的调节进行功能性检测。该项目具有高度创新性，因为它使用miRNA控制中固有的新分子机制解决了药物代谢中的发育变异。这些努力也可能对儿童和成人的个体间转运蛋白、受体和信号传导变异性产生重要影响。我们已经组建了一支在临床药理学、分子生物学和生物信息学方面具有公认专业知识的研究人员团队。作为该团队的一部分，我们可以获得大量经过适当同意的临床样本，这将使我们能够将我们的发现直接转化为人体研究。更好地了解人类肝脏CYP 450酶的发育控制机制可能会提高我们对人类药物代谢中发生的发育变化的理解。最终，这应该会导致治疗药物给药策略的改进，特别是在发育变化的关键时期。 公共卫生相关性：我们将研究导致药物不良反应和药物疗效差的潜在机制。我们将确定小内源性microRNA在肝脏药物代谢酶调节中的作用。这些研究有助于我们更好地了解药物反应的个体间差异，从而改善药物治疗。