Control of developmental switch of Cyp3a gene expression in mouse liver

小鼠肝脏 Cyp3a 基因表达发育开关的控制

基本信息

批准号：
8605879
负责人：
XIAO-BO ZHONG
金额：
$ 31.14万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
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：
2010-02-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8605879
关键词：
Acetylation Adolescence Adult Age Area Attention Birth Body Surface Area Body Weight C57BL/6 Mouse CYP3A4 gene CYP3A5 gene Cell Nucleus ChIP-on-chip Child Childhood Chromatin Chromatin Structure Chromosomes, Human, Pair 5 Cytochrome P450 DNA Data Development Developmental Gene Expression Regulation Dose Drug Regulations Ensure Environment Enzyme Gene Enzymes Epigenetic Process Euchromatin Exhibits Gene Expression Gene Expression Profile Gene Order Gene Targeting Genes Genetic Transcription Genome Goals Growth Hepatocyte Heterochromatin Histone Code Histones Human Individual Infant Intestines Kidney Knockout Mice Knowledge Literature Liver Medicine Metabolic Biotransformation Methylation Modeling Modification Mus Neonatal Nuclear Nuclear Lamina Nuclear Receptors Organ Patients Pattern Pharmaceutical Preparations Phase Physical condensation Play Positioning Attribute Process Processed Genes Protein Isoforms Protocols documentation RNA Polymerase II RNA Splicing Reaction Relative (related person)Research Role Staging Substrate Specificity Techniques Testing Therapeutic Treatment Efficacy Variant Work base cytochrome P450 3A drug metabolism epigenome epigenomics experience fetal high risk histone modification human disease male mature animal member mouse model multidisciplinary novel postnatal prenatal public health relevance response transcription factor young adult

项目摘要

DESCRIPTION (provided by applicant): The cytochrome P450 3A subfamily (CYP3A) members, such CYP3A4, CYP3A5, and CYP3A7, are the most abundant P450 enzymes expressed in human liver and intestine and are responsible for metabolizing >50% of drugs. Significant variations in CYP3A activity and gene expression have been found in liver during development, with infants and young children having different ability to metabolize many drugs than adults. Particularly, CYP3A4 and CYP3A7 exhibit profound reciprocal patterns of gene expression with a developmental switch after birth. However, the mechanisms governing the ontogenic expression of the CYP3A genes during development are unknown. Our long- term research goal is to unravel the mechanisms that control drug metabolism during development. The objective of this proposal is to identify the mechanisms controlling the ontogenic expression of the Cyp3a genes in livers during postnatal development by using mouse as a model. Our central hypothesis is that the ontogenic expression patterns of the Cyp3a genes in mouse liver are controlled by transcription factors which change epigenetic modifications at the target chromatin, and place the Cyp3a genes in distinct nuclear positions, allowing the Cyp3a genes to be turned on or off at different developmental stages. To test this hypothesis, we propose to pursue the following specific aims: (1) to establish profiles of histone modifications around the Cyp3a genes in liver cells at different ages; (2) to define chromatin condensation, nuclear positions, and associated histone modifications of the Cyp3a genes in hepatocyte nuclei at different ages; and (3) to examine the roles of the transcription factors in controlling ontogenic expression of the Cyp3a genes during liver maturation. We have assembled a multidisciplinary team and have all the techniques and mouse models ready for the proposed studies, which will help to ensure a successful completion of the proposed studies. If we prove our hypothesis is correct, the proposed study will identify transcription factors which control the ontogenic expression of the Cyp3a genes through epigenetic mechanisms. It would add greatly to our fundamental knowledge of developmental regulation of gene expression in liver development. This knowledge is particularly novel for drug metabolizing enzymes, because the areas of epigenetics and gene positioning have not received much attention with respect to the ontogeny of genes involved in drug biotransformation. Establishment of this fundamental knowledge is essential for understanding difference of drug responses between pediatric and adult patients and is important for establishing pharmaco-epigenomics based on inter-individual variation of epigenomes in personalized medicine.

描述（由申请人提供）：细胞色素P450 3A亚家族（CYP3A）成员，例如CYP3A4，CYP3A5和CYP3A7，是在人肝脏和肠道中表达的最丰富的P450酶，并负责代谢> 50％的药物。在发育过程中，在肝脏中发现了CYP3A活性和基因表达的显着差异，婴儿和幼儿代谢许多药物的能力与成人不同。尤其是，CYP3A4和CYP3A7在出生后具有发育转变表现出基因表达的深刻倒数模式。但是，开发过程中CYP3A基因的个体表达的机制尚不清楚。我们的长期研究目标是阐明在发育过程中控制药物代谢的机制。该提案的目的是确定通过使用小鼠作为模型来控制肝脏中CYP3A基因本体生成表达的机制。我们的中心假设是，小鼠肝脏中CYP3A基因的个体生成表达模式受转录因子的控制，这些转录因子改变了靶染色质的表观遗传修饰，并将CYP3A基因置于不同的核位置，从而使CYP3A基因在不同的发育阶段打开或关闭。为了检验这一假设，我们建议追求以下特定目的：（1）在不同年龄的肝细胞中建立围绕CYP3A基因的组蛋白修饰的特征；（2）定义肝细胞核中CYP3A基因的染色质凝结，核位置和相关组蛋白在不同年龄的变化；（3）检查转录因子在肝脏成熟过程中控制CYP3A基因的个体基因表达中的作用。我们已经组建了一个多学科团队，并准备好所有技术和鼠标模型进行拟议的研究，这将有助于确保成功完成拟议的研究。如果我们证明我们的假设是正确的，则提出的研究将确定通过表观遗传机制控制CYP3A基因的个体表达的转录因子。这将极大地增加我们对肝发育中基因表达的发展调节的基本知识。对于药物代谢酶，这种知识尤其是新颖的，因为表观遗传学和基因定位的区域对参与药物生物转化的基因的个体发育并没有得到太多关注。建立这种基本知识对于了解儿科和成年患者之间药物反应的差异至关重要，对于基于个性化医学表观基因组的个体差异来建立药物 - 基因组学很重要。