Developing a biomarker panel to assess choline nutritional status

开发生物标志物组来评估胆碱营养状况

• 批准号: 9916222
• 负责人: Steven H Zeisel
• 金额: $ 15.24万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-24 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916222
• 关键词: Back; Biological Assay; Biological Markers; Bolus Infusion; Chlorides; Cholesterol; Choline; Choline Deficiency; Clinical; Collection; Complement; Consumption; Data; Data Analyses; Data Collection; Diet; Dietary intake; Fasting; Fatty Liver; Fatty acid glycerol esters; Female; Food; Functional disorder; Funding; Health; Human; Image; Institute of Medicine (U.S.); Intake; Isotopes; Laboratories; Liver; Magnetic Resonance; Magnetic Resonance Spectroscopy; Masks; Mass Spectrum Analysis; Measurement; Measures; Metabolic dysfunction; Methodology; Methods; Modeling; Muscle; Nutrient; Nutritional status; Organ; Outpatients; Parents; Participant; Persons; Phase; Plasma; Postmenopause; Pregnancy; Premenopause; Procedures; Public Health Practice; Radioisotope Dilution Technique; Randomized; Risk; Sampling; Scientist; Testing; United States; Urine; Variant; base; biomarker panel; dietary supplements; elastography; experimental study; food avoidance; genetic variant; healthy volunteer; in vivo; in vivo magnetic resonance spectroscopy; male; metabolomics; nutrition; parent grant

Summary This request for a supplement to R01DK115380 is for funds for additional acquisition of magnetic resonance spectroscopy measures of choline content of liver in humans. The parent study seeks to develop a better biomarker panel that can be used by clinicians to assess a person's choline status. It has become apparent to us during the pilot phase of our studies that assessing Cho pool size using isotope dilution needs to be complemented by another accepted measure against which we can validate our metabolomic biomarker panel. We believe that using magnetic resonance spectroscopy to measure in vivo pools of soluble choline metabolites in liver needs to be added to our studies if we are to validate the metabolomic biomarker panel that we develop so as to convince clinicians that our metabolomic biomarker panel reliably predicts choline status. Choline is an important dietary supplement and essential nutrient, but there are no good validated biomarkers for assessing choline nutritional status that can be practically applied in clinical or public health practice. Choline is a required nutrient with Adequate Intake (AI) and a Tolerable Upper Limit (UL) levels set by the U.S. Institute of Medicine's Food and Nutrition Board and a Recommended Daily Intake (RDI). Given the narrow range for healthy intake of choline, given the establishment of a RDI of choline to maintain health, given the 3-fold variation in dietary intake in the US, given the effects of common genetic variants on requirements for choline and because plasma choline concentrations do not adequately reflect status, we propose that a panel of laboratory tests be developed and validated that assess choline status in humans. We will identify the biomarkers that best correlate with measurements of choline pool size using isotope dilution. Healthy volunteers (n=50 males, 50 premenopausal females and 50 postmenopausal females), as outpatients, will consume meals containing 100% of the RDI of choline (550 mg) for 2 weeks, 50% (275 mg) of the RDI of choline for 2 weeks, and 25% (137.5 mg) of the RDI of choline for 2 weeks. The order of dietary periods is randomly assigned and subjects and staff are masked. All subjects will receive all diets while on study, with a minimum of 2 weeks of “washout” between diet periods where participants go back to their normal diet. On Day 12 of each diet period, fasted subjects will consume a 250 mg bolus of choline in the form of Cho chloride-(trimethyl-d9). Plasma and urine samples will be collected for metabolomic assays and isotope dilution estimation of choline pool size and we will perform transient elastography of liver to assess liver fat. Magnetic resonance will also be used for independent assessment of choline status and liver fat. These studies will be used to determine the optimal set of biomarkers to use in calculating a choline status score.

总结 R 01 DK 115380的补充申请是为额外购置磁共振设备提供资金。 光谱测量人类肝脏的胆碱含量。家长研究旨在制定一个更好的 生物标志物面板，可用于临床医生评估一个人的胆碱状态。很明显， 在我们的研究的试点阶段，我们认为，使用同位素稀释评估Cho池的大小需要 通过另一种可接受的方法进行补充，我们可以验证我们的代谢组学生物标志物面板。 我们相信，使用磁共振波谱测量体内可溶性胆碱代谢物池， 如果我们要验证我们开发的代谢组学生物标志物面板， 从而使临床医生相信我们的代谢组学生物标志物组能够可靠地预测胆碱状态。胆碱是一种 重要的膳食补充剂和必需营养素，但没有良好的有效生物标志物用于评估 胆碱营养状况，可以实际应用于临床或公共卫生实践。胆碱是必需的 美国医学研究所（U.S. Institute of Medicine）制定的充足摄入量（AI）和可耐受上限（UL）水平的营养素 食物和营养委员会和推荐每日摄入量（RDI）。鉴于健康摄入量的范围很窄， 胆碱，鉴于建立胆碱的RDI以维持健康，鉴于膳食摄入量的3倍变化， 在美国，考虑到常见的遗传变异对胆碱需求的影响， 浓度不能充分反映现状，我们建议开发一个实验室测试小组， 评估人类胆碱状态的方法。我们将确定最相关的生物标志物 使用同位素稀释测量胆碱池大小。健康志愿者（n=50名男性，50名绝经前 女性和50名绝经后女性），作为门诊患者，将食用含有100% RDI的膳食， 胆碱（550 mg）2周，胆碱RDI的50%（275 mg）2周，以及RDI的25%（137.5 mg） 胆碱两周随机分配饮食期的顺序，受试者和工作人员均设盲。所有 受试者将在研究期间接受所有饮食，在饮食期之间至少有2周的“洗脱期”， 参与者恢复正常饮食。在每个饮食阶段的第12天，禁食受试者将消耗250 mg 以Cho氯化物-（三甲基-d9）形式的胆碱的大丸剂。将采集血浆和尿液样本， 代谢组学测定和同位素稀释估计胆碱池的大小，我们将进行短暂的 肝脏弹性成像以评估肝脏脂肪。磁共振也将用于独立评估 胆碱状态和肝脏脂肪。这些研究将用于确定用于治疗的最佳生物标志物组。 计算胆碱状态分数。