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.