Regulation of trimethylamine metabolism

背景：我的NSERC发现项目的长期目标是了解饮食胆碱和相关营养素在哺乳动物生理上的作用。胆碱是磷脂合成、膜信号、脂蛋白分泌、乙酰胆碱生物合成和单碳代谢所必需的营养物质。新兴研究已经确定，膳食胆碱可以通过肠道细菌代谢产生三甲胺（TMA），而三甲胺在肝脏氧化产生三甲胺氧化物（TMAO）。我们开发了一种新的分析血浆中TMA和TMAO的方法。此外，我们已经表明，膳食中补充胆碱会增加血浆TMAO水平；然而，这种关系取决于动物模型、饲养时间和膳食补充水平。对于这项NSERC发现拨款，我的实验室将专注于调节三甲胺代谢的因素，并将研究氧化三甲胺在各种细胞/组织中的生理作用。迄今为止，只有膳食胆碱与肠道细菌产生TMA有关；然而，我们假设饮食中的胆碱（来源和数量）和胆汁（即肝脏合成的PC）可以促进TMA/TMAO的产生。具体目的1：了解调节三甲胺/三甲胺氧化物生成的饮食和生理因素。具体目标2。了解如何改变PC代谢从头PC供应调节三甲胺/三甲胺氧化物的生产。具体目的3：通过体内和体外模型确定调节氧化三甲胺在调节脂质代谢和细胞应激中的生理后果。研究计划的影响：HQPs的培训是该研究计划的核心组成部分。HQP将培养他们的科学技能（动物处理、生物测定、细胞培养、实验设计）和专业技能（口头和书面沟通、领导能力、社区互动）。学员将被鼓励超越自己的舒适水平去思考，以确保科学的发展，并培养对科学理论和发现的热情。通过与当地NSERC发现资助实验室(博士。理查德，威林，菲尔德，柯蒂斯)与融合的专业知识。我的HQP有平等的机会参与和领导合作项目。这个NERSC发现计划将继续为我们在生命周期中胆碱营养、生物化学、生理学和代谢的基础知识提供新的贡献。本项目将采用多学科方法（包括分子、生化和生理技术）、饮食控制、新型动物模型和细胞培养来阐明氧化三甲胺的生物学效应，并了解胆碱代谢和氧化三甲胺产生之间的复杂关系。

Background: The long-term goal of my NSERC Discovery program is to understand the role of dietary choline, and related nutrients, on mammalian physiology. Choline is an essential nutrient required for phospholipid synthesis, membrane signaling, lipoprotein secretion, acetylcholine biosynthesis, and one-carbon metabolism. Emerging research has determined that dietary choline can be metabolism by intestinal bacteria to produce trimethylamine (TMA), which is oxidized in the liver to produce trimethylamine-oxide (TMAO).  We have developed a new analytical method for assessing these TMA and TMAO in plasma. Furthermore, we have shown that dietary choline supplementation increases plasma TMAO levels; however, this relationship is dependent on the animal model, length of feeding, and level of dietary supplementation. For this NSERC Discovery grant, my laboratory will focus on factors that regulate trimethylamine metabolism and will investigate the physiological role of TMAO within various cells/tissues. To date, only dietary choline has been implicated in the production of TMA from intestinal bacteria; however, we hypothesize that choline from the diet (both source and amount) and bile (i.e. PC synthesized in liver) can contribute to TMA/TMAO production. Specific Objective 1: To understand the dietary and physiological factors that modulate trimethylamine/trimethylamine-oxide production. Specific Objective 2. To understand how altering PC metabolism de novo PC supply modulates trimethylamine/trimethylamine-oxide production. Specific Objective 3: To determine physiological consequences of modulating TMAO in regulating lipid metabolism and cellular stress using in vivo and in vitro models. Impact of Research Program: The training of HQPs is a central component of this research program. HQP will develop both their scientific (animal handling, bioassays, cell culture, experimental design) and professional (verbal and written communication, leadership, community interaction) skills. Trainees will be encouraged to think beyond their comfort level to ensure scientific growth and to develop a passion for scientific theory and discovery. The research atmosphere is strengthened by collaboration with local NSERC Discovery funded laboratories (Drs. Richard, Willing, Field, Curtis) with convergent expertise. My HQP have equal opportunity to participate and lead collaborative projects. This NERSC Discovery program will continue to provide novel contributions to our fundamental knowledge of choline nutrition, biochemistry, physiology and metabolism across the lifespan. This project will use a multidisciplinary approach (including Molecular, Biochemical, and Physiological techniques), dietary manipulation, novel animal models, and cell culture to elucidate the biological effects of TMAO, and to understand the complex relationship between choline metabolism and TMAO production.