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

• 批准号: 8413218
• 负责人: XIAO-BO ZHONG
• 金额: $ 29.98万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413218
• 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

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（申请人提供）：细胞色素 P450 3A 亚家族 (CYP3A) 成员，如 CYP3A4、CYP3A5 和 CYP3A7，是人类肝脏和肠道中表达最丰富的 P450 酶，负责代谢 > 50% 的药物。在发育过程中，肝脏中的 CYP3A 活性和基因表达存在显着变化，婴儿和幼儿代谢许多药物的能力与成人不同。特别是，CYP3A4 和 CYP3A7 表现出深刻的基因表达相互模式，并在出生后发生发育转变。然而，发育过程中控制 CYP3A 基因个体表达的机制尚不清楚。我们的长期研究目标是揭示开发过程中控制药物代谢的机制。本提案的目的是以小鼠为模型，确定出生后发育过程中控制肝脏中 Cyp3a 基因个体表达的机制。我们的中心假设是，小鼠肝脏中 Cyp3a 基因的个体表达模式由转录因子控制，转录因子改变靶染色质的表观遗传修饰，并将 Cyp3a 基因置于不同的核位置，从而允许 Cyp3a 基因在不同的发育阶段打开或关闭。为了检验这一假设，我们建议追求以下具体目标：（1）建立不同年龄肝细胞中 Cyp3a 基因周围组蛋白修饰的概况； (2) 明确不同年龄肝细胞核中Cyp3a基因的染色质浓缩、核位置和相关组蛋白修饰； (3) 检查转录因子在肝脏成熟过程中控制 Cyp3a 基因个体表达的作用。我们组建了一个多学科团队，并为拟议研究准备好了所有技术和小鼠模型，这将有助于确保拟议研究的成功完成。如果我们证明我们的假设是正确的，拟议的研究将鉴定通过表观遗传机制控制 Cyp3a 基因个体表达的转录因子。它将极大地丰富我们对肝脏发育中基因表达发育调控的基础知识。这种知识对于药物代谢酶来说尤其新颖，因为表观遗传学和基因定位领域在药物生物转化所涉及的基因的个体发育方面尚未受到太多关注。这一基础知识的建立对于理解儿科和成人患者之间药物反应的差异至关重要，并且对于在个性化医疗中建立基于表观基因组个体间变异的药物表观基因组学也很重要。