Cytochrome P450-Endogenous Substrate Metabolism

细胞色素 P450-内源性底物代谢

基本信息

批准号：
7992597
负责人：
DAVID J WAXMAN
金额：
$ 9.59万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-03 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7992597
关键词：
Adult Bile Acids Binding Binding Sites Biological Assay Biological Models Bone Growth Carcinogens Catabolism Characteristics Cholesterol Chromatin Chromosomes, Human, Pair 2 Complex Computer Analysis Cytochrome P450 DNA Deoxyribonuclease I Dependence Digestion EMSA Electrophoretic Mobility Shift Assay Employee Strikes Endocrine Enzymes Epigenetic Process Event Female Gene Activation Gene Expression Gene Silencing Gene Targeting Genes Genomics Goals Growth Hormone Receptor Health Hepatic Heterogeneous Nuclear RNA Histone H3 Hormone Responsive Human Hypersensitivity Hypophysectomy IGF1 gene Immunoprecipitation Insulin-Like Growth Factor I JAK2 gene Knock-out Lead Liver Locus Control Region Maps Mediating Mediator of activation protein Medical Metabolic Biotransformation Metabolism Methods Micrococcal Nuclease Molecular Mus Nucleotides Pathway interactions Pattern Pharmaceutical Preparations Physical condensation Physiologic pulse Physiological Processes Physiology Pituitary Gland Plasma Polypeptide Hormones Protein Tyrosine Kinase Proteins Rattus Regulation Reporter Genes Response Elements Role STAT protein STAT5b Transcription Factor Sex Characteristics Signal Transduction Signaling Molecule Somatotropin Specificity Steroids Testing Time Transcription Factor 3 Transcription Initiation Site Untranslated Regions chromatin immunoprecipitation chromatin modification clinically relevant cytokine experimental analysis fatty acid oxidation gene repression genome-wide glucose uptake hepatocyte nuclear factor heterochromatin-specific nonhistone chromosomal protein HP-1 histone modification long bone male mouse model novel sex steroid hormone steroid hormone metabolism steroid metabolism transcription factor

项目摘要

DESCRIPTION (provided by applicant): The long-range goal of this project is to elucidate the endocrine regulation of hepatic cytochromes P450 (Cyps) and other enzymes that metabolize steroid hormones, bile acids, carcinogens and other lipophilic substrates of medical or environmental importance, with a focus on the actions of growth hormone (GH), a pituitary polypeptide hormone. The proposed project period uses the mouse as a model system to investigate the molecular mechanisms by which GH and its sex-dependent ultradian secretory patterns regulate Cyps and many other liver-expressed genes in a sex-specific manner. The major objective of this project is to elucidate the mechanisms that underpin the dependence of sex-specific liver gene expression on STAT5b, a signal transducer and activator of transcription that is directly activated by each incoming adult male plasma GH pulse, and on HNF41, a liver-enriched transcription factor. The studies proposed will test the hypothesis that the actions of STAT5b and HNF41 on sex-specific Cyps and other GH pulse-responsive genes involve both direct and indirect mechanisms operating through a complex regulatory network. Genome-wide approaches will be used to elucidate key components and features of the overall network through the discovery of 1) novel primary targets of GH-activated STAT5b, 2) epigenetic regulatory mechanisms controlled by GH that may lead to long-term gene silencing, and 3) transcription factors that act proximal to downstream Cyp genes. Together, these studies will elucidate key features of the intracellular events that determine the complex, GH-dependent patterns of expression of hepatic Cyps, which control metabolic processes having a major impact on liver physiology and human health, including steroid hormone metabolism, cholesterol catabolism, drug biotransformation and carcinogen activation.

描述（由申请人提供）：该项目的长期目标是阐明肝细胞色素 P450 (Cyps) 和其他代谢类固醇激素、胆汁酸、致癌物和其他具有医学或环境重要性的亲脂性底物的酶的内分泌调节，重点关注生长激素 (GH)（一种垂体多肽激素）的作用。拟议的项目期间使用小鼠作为模型系统来研究 GH 及其性别依赖性超电分泌模式以性别特异性方式调节 Cyps 和许多其他肝脏表达基因的分子机制。该项目的主要目标是阐明性别特异性肝脏基因表达对 STAT5b（一种信号转导器和转录激活剂，由每个传入的成年男性血浆 GH 脉冲直接激活）和 HNF41（一种肝脏富集的转录因子。拟议的研究将检验以下假设：STAT5b 和 HNF41 对性别特异性 Cyps 和其他 GH 脉冲反应基因的作用涉及通过复杂的调控网络运作的直接和间接机制。全基因组方法将用于通过发现 1) GH 激活的 STAT5b 的新主要靶点来阐明整个网络的关键组成部分和特征，2) GH 控制的表观遗传调控机制可能导致长期基因沉默， 3) 作用于下游 Cyp 基因附近的转录因子。这些研究将共同阐明细胞内事件的关键特征，这些事件决定肝 Cyps 复杂的、GH 依赖性表达模式，肝 Cyps 控制对肝脏生理和人类健康产生重大影响的代谢过程，包括类固醇激素代谢、胆固醇分解代谢、药物生物转化和致癌物质激活。