This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Increased biliary secretion of bile acids following high-fat intake is associated with elevated incidence of colorectal cancer, the second leading cause of cancer-related death in the US. The farnesoid X receptor (FXR) is a ligand-activated transcription factor and a member of the orphan nuclear receptor superfamily. Bile acids are endogenous ligands for FXR. Activation of FXR is essential in preventing bile-acid-induced cell damage via regulating a network of genes to inhibit bile-acid synthesis by feedback mechanism and to promote bile-acid transport by feed-forward mechanism. It is known that bile acids are promoting agents for colorectal cancer, and activation of FXR prevents bile-acid-induced toxicity. Our preliminary data, obtained from FXR-null mice, show that FXR is critical in regulating the genes involved in cell-cycle progression in colon and is important in maintaining normal intestinal morphology. My central hypothesis is that activation of FXR in the intestine inhibits cyclin-E expression, which results in the cell-cycle arrest, suppresses cell proliferation, and thus attenuates colorectal-cancer formation. Using a human colon cancer cell line and genetically modified mouse models, we plan to test our hypothesis by the following independent, yet related, specific Aims.
In Aim 1, we will define the role of FXR in cell-cycle progression and cell proliferation.
In Aim 2, we will identify the mechanism for regulating cyclin E by FXR.
In Aim 3, we will establish the role of FXR in colorectal-cancer formation in a genetically induced mouse models. The proposed research is innovative and important, because confirmation of our hypothesis will provide novel knowledge for understanding the functions of FXR, as well as a scientific basis for rational development of drugs that are FXR ligands that can be used for treating colorectal cancer.can be used for treating colorectal cancer.
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