One Carbon Nutrients and Vascular Function

我的研究项目专注于一种碳素营养素(也称为甲基营养素)的生物学。这些营养素在一种碳代谢中发挥作用，在功能上是核酸合成、NADPH生成和S-腺苷蛋氨酸合成所必需的，腺苷蛋氨酸是用于DNA、RNA、蛋白质和磷脂甲基化的甲基供体。我们研究这些营养素在生长和发育中的作用，以及这些营养素的饮食失衡如何影响代谢和生理过程。我们的发现资助研究(2009-2019年)已经确定：One碳营养素在身体成分、葡萄糖稳态、大脑和血管功能中的新/非传统作用；怀孕/哺乳期间母亲叶酸摄入量高且维生素B12状态不佳对成年后代生理/代谢的特定性别影响；One碳营养素对DNA甲基化和基因表达的特定组织影响；以及妇女和儿童饮食One碳营养素摄入量和地位的失衡。在下一个资金阶段，我们建议描述一种碳营养物质在血管内皮细胞功能中的作用。血管内皮细胞排列在血管管腔内，在调节血管对血管扩张、有丝分裂和血栓形成信号的反应中发挥作用。一氧化氮是调节内皮细胞功能的关键信号分子之一。内皮型一氧化氮合酶(ENOS)以四氢生物蝶呤(BH4)、黄素单核苷酸(FMN)/黄素腺嘌呤二核苷酸(FAD)和烟氨酸腺嘌呤二核苷酸磷酸(NADPH)为辅因子，由精氨酸合成一氧化氮。通过BH4和FMN/FAD，内皮型一氧化氮合酶和一氧化氮的合成与叶酸和核黄素代谢有关。我们的初步数据表明，血管内皮细胞叶酸代谢在血管内皮细胞功能中起作用，并且是独一无二的，不反映在肝脏和血浆中。然而，关于核黄素和叶酸在血管内皮细胞中的代谢以及饮食摄入这些营养物质如何直接影响血管内皮功能，人们知之甚少。在我们的续订申请中提出的研究将在以下目标中解决这些知识空白：1)确定核黄素状态是否调节血管内皮功能。2)确定核黄素是否与叶酸相互作用调节血管功能。3)确定妊娠核黄素状态是否影响成人的血管功能。我的研究计划的长期愿景是，通过描述一种碳营养素在哺乳动物系统中的生理效应，我们将产生以下数据：(A)提供关于食品供应和动物饲料中最佳一种碳营养素的关键信息；(B)解决加拿大食品供应中一种碳营养素强化政策的安全性；以及(C)识别和表征这些基本营养素在生理过程中的新/非传统角色。

My research program focuses on the biology of one carbon nutrients (also known as methyl nutrients). These nutrients play a role in one carbon metabolism and are functionally required for nucleic acid synthesis, NADPH generation, and S-adenosylmethionine (SAM) synthesis, a methyl donor that is used for methylation of DNA, RNA, proteins and phospholipids. We study the role of these nutrients in growth and development and how dietary imbalances in these nutrients affect metabolic and physiological processes. Our Discovery Grant research (held 2009-2019) has identified: novel/non-traditional roles for one carbon nutrients in body composition, glucose homeostasis, brain, and vascular function; sex-specific effects of high maternal folic acid intakes with suboptimal vitamin B12 status during pregnancy/lactation on adult offspring physiology/metabolism; tissue-specific effects of one carbon nutrients on DNA methylation and gene expression; and imbalances in dietary one carbon nutrient intakes and status in women and children. In the next funding period, we propose to delineate the role of one carbon nutrients in vascular endothelial function. Vascular endothelial cells line the lumen of blood vessels and function in regulating how vessels respond to vasodilatory, mitogenic, and thrombogenic cues. Nitric oxide is one of the key signalling molecules regulating endothelial cell function. Endothelial nitric oxide synthase (eNOS) synthesizes nitric oxide from arginine using tetrahydrobiopterin (BH4), flavin mononucleotide (FMN)/flavin adenine dinucleotide (FAD), and nicotinaminde adenine dinucleotide phosphate (NADPH) as cofactors. Through BH4 and FMN/FAD, eNOS and nitric oxide synthesis are metabolically linked to folate and riboflavin metabolism. Our preliminary data suggest that vascular endothelial cell folate metabolism plays a role in vascular endothelial function and is unique and not reflected in liver and plasma. However, little is known about the metabolism of riboflavin and folate in endothelial cells and how dietary intakes of these nutrients directly affect vascular endothelial function. Studies proposed in our renewal application will address these knowledge gaps in the following objectives: 1)To determine if riboflavin status regulates vascular endothelial function. 2)To determine if riboflavin interacts with folate to regulate vascular function. 3)To determine if gestational riboflavin status programs adult vascular function. The long-term vision of my research program is that by characterizing the physiological effects of one carbon nutrients in mammalian systems, we will generate data that will: (a) contribute key information about optimal one carbon nutrients in the food supply and animal feeds; (b) address the safety of one carbon nutrient fortification policies in Canada's food supply; and (c) identify and characterize novel/non-traditional roles for these essential nutrients in physiological processes.