CAREER: Endogenous Signaling Through the Farnesoid X Receptor

职业生涯：通过 Farnesoid X 受体的内源信号传导

• 批准号: 0844801
• 负责人: Gregory Tochtrop
• 金额: $ 89.31万
• 依托单位: Case Western Reserve University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2015-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0844801&HistoricalAwards=false
• 关键词: CAREER; Endogenous; Signaling; Through; Farnesoid

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.

该奖项是根据2009年的《美国复苏与再投资法》（公法111-5）资助的。科学的影响：该职业项目旨在了解胆汁酸与其细胞传感器之间的复杂反馈网络，即Farnesoid X受体（FXR）。 胆汁酸是所有哺乳动物中存在的无处不在的生理小分子，在消化中起着核心作用的大多数脊椎动物。 有趣的是，当跨物种看时，胆汁酸池的化学组成非常多样化。 即使在一个物种中，如人类所见，也可能存在重大的可变性。 该项目的目标是双重的。 首先，将使用核磁共振（NMR）光谱与合成有机化学结合开发一种方法，以开发胆汁酸探针，以了解这些分子如何通过FXR与并通过FXR进行信号。 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胆汁酸选择性的中心问题。 由于这项研究的目标是双重的，因此全球影响也是如此。 首先，该研究项目将开发NMR作为剖析复杂结合相互作用的工具，该工具将具有扩展科学家可以使用的工具库的作用。 此外，这项工作将有助于阐明有关FXR和脂质结合蛋白与胆汁酸稳态相关的更广泛问题。 更广泛的影响：该项目的教学目标与研究融为一体，但在更基本和基本的层面上着重于生物学和化学教育。 所描述的努力涵盖了从高中的大二学生到大学的大二学生，旨在将有机化学和生物化学的基本方面纳入介绍性水平。 PI还计划与当地高中老师合作，​​并将学生融入学术研究活动。 此外，一项计划详细介绍了与凯斯西部储备大学的入门班和本地同事写作教科书的同事合作，以按教授基础科学课程的方式取得垂直进展。