Protection of Intestine by the Bile Acid Receptor FXR

胆汁酸受体 FXR 对肠道的保护

• 批准号: 6850779
• 负责人: STEVEN A. KLIEWER
• 金额: $ 27.46万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6850779
• 关键词: apoptosis; bile; biological signal transduction; cell proliferation; cholanate compound; cytoprotection; detergents; fibroblast growth factor; gastrointestinal epithelium; gene expression; genetically modified animals; histology; hormone receptor; intestinal villi; laboratory mouse; protein localization; receptor expression; western blottings

DESCRIPTION (provided by applicant): The nuclear hormone receptors comprise a superfamily of ligand-activated transcription factors that regulate crucial aspects of human physiology. The study of these receptors has led to the identification of many unexpected and medically-important signaling pathways. Among the erstwhile "orphan" nuclear receptors for which physiological ligands have been discovered is the farnesoid X receptor (FXR), which is activated by bile acids. FXR is expressed in liver, where it regulates a program of genes involved in bile acid and lipid homeostasis. FXR is also highly expressed along the length of the small and large intestine; however, its function in the intestine is poorly understood. In this proposal, we hypothesize that FXR and its target gene, fibroblast growth factor (FGF)- 15, are components of a biological signal cascade that protects the mucosal layer of the intestine from the strong detergent effects of bile acids. This hypothesis is based on the following data: (i) FXR is strongly expressed in the villus epithelium and crypts; (ii) FXR-KO mice have a pronounced phenotype in the small intestine that includes blunted and dysmorphic villi and decreased number and/or size of mucus-secreting goblet cells; and, (iii) FXR dramatically induces expression of fibroblast growth factor (FGF)-15 in the villus epithelium of the small intestine. In Specific Aim 1, we will determine in which intestinal cell types FXR is expressed and whether it protects the intestine against chemical damage in vivo. In Specific Aim 2, we will characterize the expression pattern and actions of FGF-15 in the intestine and determine whether it is enteroprotective in vivo. In Specific Aim 3, the actions of FXR and FGF-15 on proliferation, apoptosis and intracellular signaling pathways will be studied in intestinal cell lines. This research will provide fundamental insights into the biology of the intestine and may have important implications for the treatment of inflammatory bowel diseases and other pathologic conditions that affect the intestinal mucosa.

描述(申请人提供)：核激素受体包括一个配体激活的转录因子超家族，调节人类生理的关键方面。对这些受体的研究导致了许多意想不到的和医学上重要的信号通路的识别。在曾经的“孤儿”核受体中，已经发现了其生理配体，其中包括法尼醇X受体(FXR)，它由胆汁酸激活。FXR在肝脏中表达，在那里它调节涉及胆汁酸和脂质动态平衡的一系列基因。FXR在小肠和大肠的长度上也高度表达；然而，它在肠道中的功能却鲜为人知。在这一建议中，我们假设FXR及其靶基因成纤维细胞生长因子-15是生物信号级联反应的组成部分，该信号级联反应保护肠道粘膜层免受胆汁酸强烈洗涤作用的影响。这一假说基于下列数据：(I)FXR在绒毛上皮和隐窝中强表达；(Ii)FXR-KO小鼠在小肠具有明显的表型，包括钝化和变形的绒毛，分泌粘液的杯状细胞数量和/或大小减少；(Iii)FXR显著诱导成纤维细胞生长因子-15在小肠绒毛上皮中表达。在具体目标1中，我们将确定FXR在哪些肠道细胞类型中表达，以及它是否在体内保护肠道免受化学损伤。在特定的目标2中，我们将表征成纤维细胞生长因子-15在肠道中的表达模式和作用，并确定其在体内是否具有肠道保护作用。在具体目标3中，将研究FXR和成纤维细胞生长因子-15对肠道细胞系的增殖、凋亡和细胞内信号通路的作用。这项研究将提供对肠道生物学的基本见解，并可能对治疗炎症性肠病和其他影响肠道粘膜的病理条件具有重要意义。