Developmental Regulation of Drug Processing Genes

药物加工基因的发育调控

基本信息

批准号：
7777148
负责人：
CURTIS DEAN KLAASSEN
金额：
$ 63.31万
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 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7777148
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 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. PUBLIC HEALTH RELEVANCE: The proposed studies are of importance and an under-investigated area of regulatory mechanisms of the developmental expression patterns of genes important in the absorption, distribution, metabolism, and excretion of therapeutic drugs. Thus, the findings are expected to be applicable to the improvement of efficacy and safety of pediatric pharmacology.

描述（由申请人提供）：尽管最近在理解药物加工基因的表达模式和调节机制方面快速进展，即成人药物代谢酶和转运蛋白，但在儿科时期对这些酶和转运蛋白的了解鲜为人知。长期目标是了解药物加工基因的个体调节机制，以便在儿童中可以实现有效且安全的药物治疗。已知几个因素对于正常发育至关重要，包括肝细胞核因子11（HNF11），Farneoid X受体（FXR），生长激素（GH）信号传导和表观遗传影响。早期肝发育的主要调节剂HNF11调节大量药物加工基因的肝表达。在很大程度上通过FXR介导的胆汁酸信号通路的启动是围产期肝发育的标志。 GH对于产后肝基因表达和成熟是必不可少的。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，在发展小鼠肝脏中，药物加工基因和转录因子以不同的动态模式表达，并与表观遗传学特征相关。该提案的目的是阐明小鼠药物加工基因的原生基因表达的调节机制。该提案的理由是，其成功完成将产生基本知识，这将成为进一步了解人类儿科药理学的基础。中心假设是：药物加工基因的发育调控是由激素调节的顺序事件，该事件激活转录因子以修饰表观遗传特征并调节基因表达。该假设将以2个目标进行检验。 AIM 1将确定药物加工基因的个体基因表达模式以及与转录因子和表观遗传学特征的相关性。将检查雄性小鼠肝脏中主要I/II酶的相对mRNA表达与肠道和肾脏中的药物转运蛋白的相对mRNA表达，并与转录因子和染色体修饰的表达（全基因组DNA甲基化和组蛋白修饰）相关。 AIM 2将使用相同的工作策略来阐明转录因子和GH在HNF11-NULL，FXR-NULL和GH缺乏症（LIT/LIT）小鼠中确定药物加工基因的肝表达的作用。这项研究是新颖的，因为它将采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学特征和肝脏个体生成表达。这项研究很重要，因为对小儿阶段的肝药物加工基因的调节知之甚少。这项研究的结果将：1）提供有关肝脏，肾脏和肠受到药物加工基因和核受体的个体基因表达模式的基础知识； 2）有助于了解激素和核受体的围产期改变如何通过调节表观遗传学特征来影响药物加工基因的阶段特异性和长期表达。公共卫生相关性：拟议的研究至关重要，并且在对治疗药物的吸收，分布，代谢和排泄中很重要的基因发育表达模式的调节机制不足。因此，这些发现有望适用于改善小儿药理学的功效和安全性。