Developing a biomarker panel to assess choline nutritional status

摘要 请求对R01DK115380进行补充是为了获得额外的磁共振检查资金 人体肝脏胆碱含量的光谱分析。家长研究试图开发一种更好的 临床医生可以用来评估一个人的胆碱状况的生物标记物小组。很明显， 在我们研究的试点阶段，使用同位素稀释度评估CHO池大小需要 再加上另一个公认的标准，我们可以对照该标准来验证我们的代谢生物标记物小组。 我们认为，使用磁共振波谱来测量体内可溶胆碱代谢物池 如果我们要验证我们开发的代谢生物标记物小组，我们的研究中需要增加肝脏中的 以使临床医生相信我们的代谢生物标记物小组可以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，但目前还没有有效的生物标志物来评估 可实际应用于临床或公共卫生实践的胆碱营养状况。胆碱是必需的 具有足够摄入量(AI)和可容忍上限(UL)水平的营养素，由美国医学研究所设定 食物和营养委员会和每日建议摄入量(RDI)。考虑到健康摄入的范围很窄 胆碱，鉴于建立了维持健康的胆碱RDI，鉴于饮食摄入量的3倍变化 在美国，考虑到常见基因变异对胆碱需求的影响，以及因为血浆胆碱 浓度不能充分反映状态，我们建议开发一组实验室测试并 验证了评估人类胆碱状态的方法。我们将确定与之最相关的生物标记物 用同位素稀释法测量胆碱池的大小。健康志愿者(男性50例，绝经前50例) 女性和50名绝经后女性)，作为门诊患者，将摄入100%的RDI 胆碱550mg2周，50%(275mgRDI2周)，25%(137.5 mg)RDI2周 胆碱治疗2周。饮食周期的顺序是随机分配的，受试者和工作人员都戴着面具。全 受试者将在学习期间接受所有的饮食，在以下节食期之间至少有2周的“冲刷” 参与者回到他们正常的饮食中。在每个节食期的第12天，禁食的受试者将摄入250毫克 以三甲基-D9为形式的胆碱。将采集血浆和尿液样本用于 代谢分析和同位素稀释估计胆碱池的大小，我们将进行瞬时 肝脏弹性成像以评估肝脏脂肪。磁共振也将用于独立评估 胆碱状况和肝脏脂肪。这些研究将被用来确定用于治疗的最佳生物标志物集合 计算胆碱状态分数。

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.