权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Novel in vivo regulatory mechanisms of human CYP3A4

人CYP3A4的新型体内调节机制

基本信息

批准号：
8816070
负责人：
Romi Ghose
金额：
$ 18.73万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-15 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8816070
关键词：
3&apos Untranslated Regions Antibodies Binding Binding Sites Bioinformatics Biological Assay CYP3A4 gene Cardiovascular Diseases Cells Chemicals Chromatin Communicable Diseases Complex Cytochrome P450 Cytochrome P450 3A4 DNA DNase-I Footprinting Development Diabetes Mellitus Disease Down-Regulation Drug Interactions Endotoxins Enhancers Environment Enzymes Epigenetic Process Future Gene Expression General Transcription Factors Genome Goals Health HepG2 High-Throughput Nucleotide Sequencing Human Image Immunoprecipitation In Vitro Individual Infection Inflammation Mediators Lead Ligands Lipopolysaccharides Liver Liver diseases Luciferases Malignant Neoplasms Maps Measures Mediating Messenger RNA MicroRNAs Microarray Analysis Modification Molecular Mus Nuclear Orphan Receptor Nuclear Receptors Patients Pharmaceutical Preparations Plasmids Post-Transcriptional Regulation Proteins RNA RNA-Protein Interaction Reaction Regulation Regulatory Element Rifampin Risk Role Safety Site Techniques base chromatin immunoprecipitation chromatin modification crosslink crosslinking and immunoprecipitation sequencing cytokine deep sequencing drug metabolism gel mobility shift assay genome-wide hepatocyte nuclear factor improved in vivo inflammatory marker mRNA Expression mutant novel pregnane X receptor prevent promoter protein expression research study transcription factor

项目摘要

DESCRIPTION (provided by applicant): Cytochrome P450 (CYP) 3A4 is the most abundant CYP enzyme in the human liver, and it metabolizes ~60% of known drugs. CYP3A4-mediated drug metabolism is impaired in patients with infections, diabetes, cancer, cardiovascular diseases, liver disorders and many other diseases. Disruptions in drug metabolism in diseases are associated with induction of inflammatory markers and reductions in expression of CYP enzymes. Thus, in most patients, medications are exposed to a micro-environment where inflammatory mediators are activated. This increases the risks of drug-drug interactions and adverse drug reactions in these patients. The objective of this exploratory proposal is to perform genome-wide mapping and bioinformatics analysis to identify key regulators involved in down-regulation of human CYP3A4 enzymes in vivo. CYP3A4 gene expression is regulated by basal transcription factors as well as nuclear receptors (NRs). In vitro studies have shown that CYP3A4 expression is also regulated by microRNAs (miRNAs). Thus, down-regulation of CYP3A4 enzymes may be a cumulative effect of transcriptional and post-transcriptional modifications by transcription factors, NRs and/or miRNAs. Our central hypothesis is that down-regulation of CYP3A4 expression is controlled by transcription factor/NR-associated epigenetic modifications at the target chromatin as well as by changes in miRNA binding to CYP3A4 mRNA. The first aim of this proposal will examine the hypothesis that down- regulation of CYP3A4 gene is controlled by transcription factor/NR-associated epigenetic modifications at the target chromatin. The second aim will determine the role of miRNAs in down-regulation of CYP3A4 enzymes in vivo. CYP3A4 expression can be activated by diverse chemicals which induce NRs, including pregnane X receptor (PXR). On the other hand, CYP3A4 can be down-regulated by inflammatory mediators including cytokines and the bacterial endotoxin, lipopolysaccharide (LPS) which are associated with diseases. To identify the key regulators involved in alteration of CYP3A4 enzymes, our strategy is to utilize a combined approach of CYP3A4 induction by PXR ligand (e.g. PCN) and CYP3A4 down-regulation by LPS. The proposed studies using genome-based approaches can unravel novel regulatory elements which contribute to down-regulation of human CYP3A4 enzymes in vivo. These regulators can then be targeted to prevent undesirable effects of drugs due to changes in CYP3A4-mediated drug metabolism. Ultimately, this can lead to the development of new strategies to improve the safety of medications in individual patients.

描述（由申请人提供）：细胞色素P450（CYP）3A4是人体肝脏中含量最丰富的CYP酶，可代谢约60%的已知药物。CYP3A4介导的药物代谢在感染、糖尿病、癌症、心血管疾病、肝脏疾病和许多其他疾病的患者中受损。疾病中药物代谢的破坏与炎症标志物的诱导和炎症酶表达的减少有关。因此，在大多数患者中，药物暴露于炎症介质被激活的微环境中。这增加了这些患者发生药物相互作用和药物不良反应的风险。该探索性建议的目的是进行全基因组定位和生物信息学分析，以确定参与体内人CYP3A4酶下调的关键调节因子。CYP3A4基因表达受基础转录因子以及核受体（NR）调节。体外研究表明，CYP3A4的表达也受microRNA（miRNAs）的调控。因此，CYP3A4酶的下调可能是转录因子、NR和/或miRNA的转录和转录后修饰的累积效应。我们的中心假设是，CYP3A4表达的下调是由靶染色质的转录因子/NR相关表观遗传修饰以及与CYP3A4 mRNA结合的miRNA的变化控制的。本提案的第一个目的是检验CYP3A4基因的下调受靶染色质处的转录因子/NR相关表观遗传修饰控制的假设。第二个目标是确定miRNA在体内下调CYP3A4酶中的作用。CYP3A4的表达可被多种诱导NR的化学物质激活，包括CYP3A4 X受体（PXR）。另一方面，CYP3A4可被与疾病相关的炎症介质包括细胞因子和细菌内毒素、脂多糖（LPS）下调。为了鉴定参与CYP3A4酶改变的关键调节剂，我们的策略是利用PXR配体（例如PCN）诱导CYP3A4和LPS下调CYP3A4的组合方法。使用基于基因组的方法的拟议研究可以解开新的调节元件，有助于下调人CYP3A4酶在体内。然后，这些调节剂可以被靶向以防止由于CYP3A4介导的药物代谢的变化而引起的药物不良反应。最终，这可以导致新策略的开发，以提高个体患者的药物安全性。