Identification of Genes Activated By Bile Acids

胆汁酸激活基因的鉴定

• 批准号: 7101101
• 负责人: Peter A Edwards
• 金额: $ 37.72万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7101101
• 关键词: acetaminophen; adrenal glands; bactericidal immunity; blood glucose; cell line; cholanate compound; chromatin immunoprecipitation; cytoprotection; farnesyl compound; gene expression; genetic mapping; genetic regulation; genetically modified animals; glucose metabolism; hepatotoxin; laboratory mouse; liver metabolism; nuclear receptors; protein isoforms; protein structure function; receptor expression; septic shock; steroid biosynthesis; transcription factor

DESCRIPTION (provided by applicant): The major goals of our research have been to identify the mechanisms of activation of the farnesoid X receptor (FXR) and to define its role in regulating metabolic pathways. To this end, we have identified four human and murine FXR transcripts derived from a single gene that encode four different protein isoforms. Our identification of a four amino acid motif (MYTG), located immediately adjacent to the DNA binding domain of two of the four isoforms, dramatically altered our thinking about this transcription factor; new and exciting data suggest that the presence of this motif affects transactivation of certain hepatic and adrenal genes. We have recently discovered that activated FXR has a pronounced effect on glucose metabolism in mice and is highly protective against the acute hepatoxicity produced by toxic xenobiotics and from the toxic effects of IPS (lipopolysaccharide). We have also recently obtained evidence that FXR regulates a number of steroidogenic genes, suggesting a functional role for FXR in the adrenal cortex. Based on these data, generated during the current grant period, we propose to conduct mechanistic studies to elucidate the roles of FXR in i) the control of plasma glucose levels and hepatic glucose metabolism, ii) the control of plasma and hepatic lipid levels, iii) protection of the liver from damage induced by xenobiotics such as acetaminophen, iv) protecting mice from endotoxin shock and bacterial infection and v) the regulation of target genes in adrenal steroidogenic cells. These studies will be aided by the availability of FXR transgenic and FXR-/- mice, and mice lacking FXR in the liver or intestine, and adenovirus expressing individual FXR isoforms. To complement these approaches, mechanistic studies will be conducted to elucidate the function of the MYTG motif present in two of the four FXR isoforms. Taken together, these studies will identify novel regulatory mechanisms by which FXR isoforms activate transcription. In addition, these studies will elucidate the role of FXR in glucose, steroid and drug metabolism and in resistance to endotoxin.

描述（由申请人提供）：我们研究的主要目标是确定法呢醇 X 受体 (FXR) 的激活机制并确定其在调节代谢途径中的作用。为此，我们鉴定了源自编码四种不同蛋白质亚型的单个基因的四种人类和鼠类 FXR 转录本。我们对四个氨基酸基序 (MYTG) 的鉴定，该基序紧邻四个亚型中两个的 DNA 结合域，极大地改变了我们对这种转录因子的看法；新的令人兴奋的数据表明，该基序的存在会影响某些肝脏和肾上腺基因的反式激活。我们最近发现，活化的 FXR 对小鼠的葡萄糖代谢有显着影响，并且对有毒异生物质产生的急性肝毒性和 IPS（脂多糖）的毒性作用具有高度保护作用。我们最近还获得了 FXR 调节许多类固醇生成基因的证据，表明 FXR 在肾上腺皮质中发挥功能作用。基于当前资助期间产生的这些数据，我们建议进行机制研究，以阐明 FXR 在 i) 血浆葡萄糖水平和肝葡萄糖代谢的控制，ii) 血浆和肝脂质水平的控制，iii 中的作用) 保护肝脏免受对乙酰氨基酚等异生物质引起的损害，iv) 保护小鼠免受内毒素休克和细菌感染，v) 调节肾上腺类固醇生成细胞中的靶基因。这些研究将得到 FXR 转基因小鼠和 FXR-/- 小鼠、肝脏或肠道缺乏 FXR 的小鼠以及表达单个 FXR 亚型的腺病毒的帮助。为了补充这些方法，将进行机制研究以阐明四种 FXR 同种型中的两种中存在的 MYTG 基序的功能。总而言之，这些研究将确定 FXR 亚型激活转录的新调控机制。此外，这些研究将阐明 FXR 在葡萄糖、类固醇和药物代谢以及内毒素抵抗中的作用。