Cytochrome P450-Endogenous Substrate Metabolism

细胞色素 P450-内源性底物代谢

• 批准号: 8209211
• 负责人: DAVID J WAXMAN
• 金额: $ 46.3万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8209211
• 关键词: Adult; Bile Acids; Biological Models; Carcinogens; Catabolism; Cholesterol; Complex; Cytochrome P450; Dependence; Endocrine; Enzymes; Epigenetic Process; Event; Gene Expression; Gene Silencing; Genes; Goals; Health; Hepatic; Human; Lead; Liver; Medical; Metabolic Biotransformation; Metabolism; Molecular; Mus; Names; Pattern; Pharmaceutical Preparations; Physiologic pulse; Physiology; Pituitary Gland; Plasma; Polypeptide Hormones; Principal Investigator; Regulation; Research; Resource Sharing; STAT protein; Somatotropin; Testing; Transcription Factor 3; genome-wide; male; novel; programs; sex; steroid hormone; steroid hormone metabolism; transcription factor

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.

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.拟议的项目时期使用小鼠作为模型系统来研究GH及其性别依赖性超大分泌模式的分子机制，以性别特异性的方式调节CYP和许多其他肝脏表达的基因。该项目的主要目的是阐明基于性别特异性肝基因表达对STAT5B的依赖性的机制，STAT5B是一种信号换能器和转录的激活因子，由每个传入的成年男性血浆GH脉冲直接激活，以及对肝脏增强的转录因子HNF41的HNF41。提出的研究将检验以下假设：STAT5B和HNF41对性别特异性CYP和其他GH脉冲响应基因的作用涉及通过复杂的调节网络运行的直接和间接机制。通过发现1）GH激活的STAT5B的新主要靶标，2）由GH控制的表观遗传调节机制通过发现，将使用全基因组的方法来阐明整个网络的关键组成部分和特征，而GH控制的表观遗传调节机制可能会导致长期基因沉默，而3）转录因子与下降cyp基因相邻。总之，这些研究将阐明细胞内事件的关键特征，这些事件决定了肝CYP的复杂，依赖性依赖性的表达模式，这些模式控制了对肝脏生理和人类健康的代谢过程，包括类固醇激素代谢，胆固醇，分解代谢，药物生物转移和交易生物转化和致癌激活。