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Developmental Regulation of Drug Processing Genes

药物加工基因的发育调控

基本信息

批准号：
8663696
负责人：
Yue Cui
金额：
$ 3.67万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-03 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8663696
关键词：
Abbreviations Acetylation Adult Affect Applications Grants Area Bile Acids Child Childhood Chromatin Chromosomes Clinical Consensus DNA Methylation DNA Sequence Development Developmental Gene Drug Regulations Elements Endocrine Ensure Enzymes Epigenetic Process Event Excretory function Foundations Future Gene Expression Gene Expression Profile Gene Expression Regulation Gene Targeting Genes Genetic Genetic Transcription Goals Growth Hormone Receptor HNF-1alpha Hepatic Histones Hormonal Hormones Human Individual Intestines Kidney Knowledge Lead Life Liver Long-Term Effects Mediating Messenger RNA Metabolism Methylation Modification Molecular Mus Newborn Infant Nuclear Hormone Receptors Nuclear Receptors Nutrient Pattern Perinatal Pharmaceutical Preparations Pharmacotherapy Phase Process Processed Genes Reaction Receptor Signaling Regulation Relative (related person)Role Safety Signal Pathway Signal Transduction Site Small Intestines Somatotropin Staging Techniques Testing Therapeutic Tissues Variant Work Xenobiotics absorption activating transcription factor chromatin immunoprecipitation chromatin modification constitutive androstane receptor drug mechanism experience genome-wide growth hormone deficiency hepatocyte nuclear factor high risk histone modification imprint improved interdisciplinary approach liver function mRNA Expression male mouse model multidisciplinary novel pediatric pharmacology postnatal pregnane X receptor public health relevance receptor sensor transcription factor

项目摘要

DESCRIPTION (provided by applicant): Despite recent rapid progress in understanding the expression patterns and regulatory mechanisms of drug processing genes, namely drug metabolizing enzymes and transporters in adults, little is known about these in the pediatric period. The long-term goal is to understand mechanisms of ontogenic regulation of drug processing genes, so that efficacious and safe drug treatments can be achieved in children. Several factors are known to be essential for normal development, including hepatocyte nuclear factor 11 (HNF11), farnesoid X receptor (FXR), growth hormone (GH) signaling, and epigenetic influences. HNF11, a master regulator of early liver development, regulates hepatic expression of a large battery of drug processing genes. Initiation of bile-acid signaling pathways, mediated largely via the FXR, is a hallmark of perinatal liver development. GH is essential for postnatal hepatic gene expression and maturation. The accessibility of transcription factors to the target genes is largely determined by the methylation/acetylation status of histones and DNA sequences. Preliminary studies illustrate that in developing mouse livers, drug processing genes and transcription factors are expressed in distinct dynamic patterns and correlate with epigenetic signatures. The objective of this proposal is to elucidate the regulatory mechanisms of ontogenic expression of drug processing genes in mice. The rationale of this proposal is that its successful completion will generate basic knowledge that will serve as the foundation for further understanding pediatric pharmacology in humans. The central hypothesis is: developmental regulation of drug processing genes is a sequential event regulated by hormones, which activate transcription factors to modify epigenetic signatures and regulate gene expression. This hypothesis will be tested in 2 aims. Aim 1 will determine the ontogenic expression patterns of drug processing genes and the correlation with transcription factors and epigenetic signatures. The relative mRNA expression of major phase I/II enzymes and drug transporters in male mouse livers versus intestine and kidney will be examined, and correlated with expression of transcription factors and chromosome modifications (genome-wide DNA methylation and histone modifications). Aim 2 will elucidate roles of transcription factors and GH in determining ontogenic hepatic expression of drug processing genes in HNF11-null, FXR-null, and GH deficiency (lit/lit) mice using the same working strategy. This study is novel, because it will use a genome-wide approach to elucidate how alterations of hormones and transcription factors modulate epigenetic signatures and hepatic ontogenic expression of drug processing genes. This study is significant, because little is known about the regulation of hepatic drug processing genes in pediatric stages. Results from this study will: 1) provide basic knowledge on the ontogenic expression patterns of drug processing genes and nuclear receptors in liver, kidney, and intestine; and 2) help to understand how perinatal alterations in hormones and nuclear receptors, via modulating epigenetic signatures, affect stage-specific and long-term expression of drug processing genes.

描述（由申请人提供）：尽管最近在理解药物加工基因（即成人中的药物代谢酶和转运蛋白）的表达模式和调控机制方面取得了快速进展，但对儿科时期的这些基因知之甚少。长期目标是了解药物加工基因的个体发育调控机制，以便在儿童中实现有效和安全的药物治疗。已知几种因子对正常发育至关重要，包括肝细胞核因子11（HNF 11）、法尼醇X受体（FXR）、生长激素（GH）信号传导和表观遗传影响。HNF 11是早期肝脏发育的主要调节因子，调节大量药物加工基因的肝脏表达。胆汁酸信号通路的启动，主要通过FXR介导，是围产期肝脏发育的标志。生长激素是出生后肝脏基因表达和成熟所必需的。转录因子对靶基因的可及性在很大程度上取决于组蛋白和DNA序列的甲基化/乙酰化状态。初步研究表明，在小鼠肝脏发育过程中，药物加工基因和转录因子以不同的动态模式表达，并与表观遗传特征相关。本研究的目的是阐明药物加工基因在小鼠个体发育过程中表达的调控机制。该提案的基本原理是，其成功完成将产生基础知识，这些知识将作为进一步了解人类儿科药理学的基础。核心假设是：药物加工基因的发育调控是由激素调节的顺序事件，激素激活转录因子以修饰表观遗传标记并调节基因表达。这一假设将在2个目标中进行检验。目的1研究药物加工基因的个体发育表达模式及其与转录因子和表观遗传标记的相关性。将检查雄性小鼠肝脏与肠和肾脏中主要I/II期酶和药物转运蛋白的相对mRNA表达，并将其与转录因子表达和染色体修饰（全基因组DNA甲基化和组蛋白修饰）相关联。目的2将阐明转录因子和GH在确定HNF 11-null，FXR-null和GH缺乏（lit/lit）小鼠中药物加工基因的个体发生性肝脏表达中的作用。这项研究是新颖的，因为它将使用全基因组方法来阐明激素和转录因子的改变如何调节药物加工基因的表观遗传特征和肝脏个体发育表达。这项研究是有意义的，因为我们对儿科阶段肝脏药物加工基因的调控知之甚少。本研究的结果将：1）提供关于药物加工基因和核受体在肝脏，肾脏和肠道中的个体发育表达模式的基本知识;和2）帮助理解激素和核受体的围产期改变如何通过调节表观遗传特征影响药物加工基因的阶段特异性和长期表达。