Cytochrome P450-Endogenous Substrate Metabolism

描述(申请人提供)：这个项目的长期目标是阐明肝脏细胞色素P450(Cyps)和其他酶的内分泌调节，这些酶代谢类固醇激素、胆汁酸、致癌物和其他对医学或环境具有重要意义的脂类底物，重点关注生长激素(GH)的作用，生长激素是一种脑下垂体多肽激素。该项目以小鼠为模型系统，研究生长激素及其性别依赖的超常分泌模式以性别特异性方式调节细胞色素P450和许多其他肝脏表达基因的分子机制。该项目的主要目的是阐明性别特异性肝脏基因表达依赖于STAT5b和HNF41的机制。STAT5b是一种信号转导和转录激活因子，由每个成年男性血浆GH脉冲直接激活。建议的研究将检验这样一种假设，即STAT5b和HNF41对性别特异的细胞色素P450和其他生长激素脉冲反应基因的作用涉及通过复杂的调控网络进行操作的直接和间接机制。全基因组的方法将被用来通过发现1)生长激素激活的STAT5b的新的主要靶点，2)由生长激素控制的可能导致长期基因沉默的表观遗传调控机制，以及3)作用于下游Cyp基因近端的转录因子，来阐明整个网络的关键成分和特征。总之，这些研究将阐明细胞内事件的关键特征，这些事件决定了肝脏细胞周期蛋白的复杂的、生长激素依赖的表达模式，这些事件控制着对肝脏生理和人类健康有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激活。

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.