Regulation of trimethylamine metabolism

背景：我的NSERC发现计划的长期目标是了解饮食中胆碱和相关营养物质对哺乳动物生理的作用。胆碱是磷脂合成、膜信号转导、脂蛋白分泌、乙酰胆碱生物合成和一碳代谢所必需的营养物质。新的研究已经确定，饮食中的胆碱可以被肠道细菌代谢生成三甲胺(TMA)，三甲胺在肝脏中被氧化生成三甲胺氧化物(TMAO)。我们开发了一种新的分析方法来评估血浆中的这些TMA和TMAO。此外，我们还表明，膳食胆碱补充会增加血浆TMAO水平；然而，这种关系取决于动物模型、喂养时间和膳食补充水平。对于这笔NSERC发现基金，我的实验室将专注于调节三甲胺代谢的因素，并将研究TMAO在各种细胞/组织中的生理作用。到目前为止，只有饮食中的胆碱与肠道细菌产生TMA有关；然而，我们假设来自饮食(来源和数量)和胆汁(即在肝脏中合成的PC)的胆碱可能有助于TMA/TMAO的产生。具体目标1：了解调节三甲胺/三甲胺氧化物产生的饮食和生理因素。具体目标2.了解改变PC新陈代谢从头开始PC供应如何调节三甲胺/三甲胺氧化物的产生。具体目标3：利用体内和体外模型，确定调节TMAO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：HQP的培训是本研究计划的核心组成部分。HQP将同时发展他们的科学技能(动物处理、生物分析、细胞培养、实验设计)和专业技能(口头和书面沟通、领导力、社区互动)。将鼓励学员超越他们的舒适水平进行思考，以确保科学成长，并培养对科学理论和发现的热情。通过与NSERC发现资助的当地实验室(Richard、Wisting、field、Curtis博士)进行合作，具有共同的专业知识，研究氛围得到了加强。我的总部经理有平等的机会参与和领导协作项目。NERSC探索计划将继续为我们终身学习胆碱营养、生物化学、生理学和新陈代谢的基础知识做出新的贡献。该项目将使用多学科方法(包括分子、生化和生理技术)、饮食操作、新型动物模型和细胞培养来阐明TMAO的生物学效应，并了解胆碱代谢和TMAO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.