Protection of Intestine by the Bile Acid Receptor FXR

描述（由申请人提供）：核激素受体包括调节人体生理学关键方面的配体激活转录因子超家族。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鉴定。在已经发现的生理配体的以前的“孤儿”核受体中，是法尼醇X受体（FXR），其被胆汁酸激活。FXR在肝脏中表达，在那里它调节参与胆汁酸和脂质稳态的基因程序。FXR也沿小肠和大肠的长度沿着高度表达;然而，其在肠中的功能知之甚少。在这个提议中，我们假设FXR及其靶基因成纤维细胞生长因子（FGF）-15是生物信号级联的组成部分，该生物信号级联保护肠粘膜层免受胆汁酸的强洗涤剂作用。该假设基于以下数据：（i）FXR在绒毛上皮和隐窝中强烈表达;（ii）FXR-KO小鼠在小肠中具有明显的表型，包括钝化和畸形绒毛以及分泌粘液的杯状细胞的数量和/或大小减少;和（iii）FXR显著诱导小肠绒毛上皮中成纤维细胞生长因子（FGF）-15的表达。在具体目标1中，我们将确定FXR在哪些肠细胞类型中表达，以及它是否保护肠道免受体内化学损伤。在具体目标2中，我们将描述FGF-15在肠道中的表达模式和作用，并确定其是否具有体内肠道保护作用。在具体目标3中，将在肠细胞系中研究FXR和FGF-15对增殖、凋亡和细胞内信号传导途径的作用。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粘膜的病理条件具有重要意义。

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.