CAREER: Endogenous Signaling Through the Farnesoid X Receptor

Case Western Reserve University, Cleveland OH

Investigators

Abstract

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5). Scientific Impacts: This CAREER project aims to understand the complex feedback network between bile acids and their cellular sensor, the farnesoid X receptor (FXR). Bile acids are ubiquitous physiologic small molecules present in all mammals and most vertebrates that play a central role in digestion. Interestingly, when looking across species, the chemical composition of the bile acid pool is quite diverse. Even within a species, there can be significant variability, as seen in humans. The goals of this project are twofold. First, an approach will be developed using nuclear magnetic resonance (NMR) spectroscopy in conjunction with synthetic organic chemistry to develop bile acid probes to understand how these molecules interact with and signal through FXR. Second, these probes will be used to study central questions of bile acid selectivity between FXR and a class of lipid binding proteins that also bind bile acids. As the goals of this research are twofold, so is the global impact. First, this research project will develop NMR as a tool for dissecting complex binding interactions, which will have the effect of expanding the repertoire of tools that can be used by scientists to study such systems. Further, this work will help to illuminate broader questions about the function of FXR and lipid binding proteins as they relate to bile acid homeostasis. Broader Impacts: The pedagogical goals of this project integrate with the research, but focus on biological and chemical education at a more basic and fundamental level. The audience of the described efforts spans from sophomores in high school to sophomores in college and aim to integrate fundamental aspects of both organic chemistry and biochemistry into basic courses at an introductory level. The PI also plans to partner with local high school teachers and integrate their students into scholarly research activities. In addition, a plan is detailed to work with colleagues who are engaged in writing textbooks for introductory classes and local colleagues at Case Western Reserve University to make vertical progress in the way that basic science courses are taught.