ORPHAN NUCLEAR RECEPTORS IN CHOLESTEROL HOMEOSTASIS

胆固醇稳态中的孤儿核受体

• 批准号: 6381792
• 负责人: Barry M. Forman
• 金额: $ 35.7万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6381792
• 关键词: cholanate compound; cholesterol; clinical research; gene mutation; genetically modified animals; homeostasis; human subject; laboratory mouse; lipid metabolism; nuclear receptors; nucleic acid sequence; receptor binding; steroid biosynthesis; transcription factor

The rate of cholesterol degradation is tightly regulated in vivo. The major metabolic pathway for the degradation of cholesterol is via conversion to bile acids. The end-products of this pathway, the bile acids, are negative regulators of cholesterol degradation. This is an important feedback loop that regulates cholesterol homeostasis. Recent evidence indicates that the nuclear receptor FXR is a bile acid receptor that may be involved in this process. This proposal will involve a detailed analysis of the role of FXR in regulating cholesterol homeostasis. This will include a detailed description of the precise signaling molecules that bind to FXR and an analysis of the target genes that are modulated by this receptor. The mechanism of FXR activation or repression of gene expression will also be studied. Finally, the physiological function of FXR ligands will be studied through a combination of pharmacologic and genetic approaches.

胆固醇降解的速率在体内受到严格调节。 胆固醇降解的主要代谢途径是通过 转化为胆汁酸。该途径的最终产物，胆汁酸是 胆固醇降解的负调节剂。这是一个重要的反馈 调节胆固醇稳态的循环。最近的证据表明 核受体FXR是一种胆汁酸受体，可能涉及 过程。该建议将涉及FXR在中的作用的详细分析 调节胆固醇稳态。这将包括一个详细描述 与FXR结合的精确信号分子和目标分析 该受体调节的基因。 FXR激活的机制或 还将研究基因表达的抑制。最后，生理学 FXR配体的功能将通过药理学的组合研究 和遗传方法。