CAREER: Endogenous Signaling Through the Farnesoid X Receptor

该奖项是根据2009年美国复苏和再投资法案（公法111-5）资助的。科学影响：该职业生涯项目旨在了解胆汁酸及其细胞传感器，法尼醇X受体（FXR）之间的复杂反馈网络。 胆汁酸是存在于所有哺乳动物和大多数脊椎动物中的普遍存在的生理小分子，其在消化中起核心作用。 有趣的是，当跨物种观察时，胆汁酸库的化学组成是相当多样化的。 即使在一个物种内，也可能存在显著的变异性，就像在人类身上看到的那样。 该项目的目标是双重的。 首先，将开发一种方法，使用核磁共振（NMR）光谱结合合成有机化学来开发胆汁酸探针，以了解这些分子如何与FXR相互作用并通过FXR发出信号。 其次，这些探针将用于研究FXR和一类也结合胆汁酸的脂质结合蛋白之间的胆汁酸选择性的中心问题。 由于这项研究的目标是双重的，所以全球影响也是如此。 首先，该研究项目将开发NMR作为解剖复杂结合相互作用的工具，这将扩大科学家可用于研究此类系统的工具库。 此外，这项工作将有助于阐明有关FXR和脂质结合蛋白的功能的更广泛的问题，因为它们与胆汁酸稳态有关。 更广泛的影响：该项目的教学目标与研究相结合，但侧重于生物和化学教育在更基本和基础的水平。 所描述的努力的受众从高中的学生到大学的学生，旨在将有机化学和生物化学的基本方面融入基础课程的入门级。 PI还计划与当地高中教师合作，将他们的学生融入学术研究活动。 此外，还详细制定了一项计划，与凯斯西储大学从事编写入门课程教科书的同事和当地同事合作，在基础科学课程的教学方式上取得纵向进展。

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.