Serum Metabolomic/Proteomic Profiles in CALERIE

CALERIE 中的血清代谢组学/蛋白质组学分析

• 批准号: 7102005
• 负责人: BRUCE S KRISTAL
• 金额: $ 37.82万
• 依托单位: WINIFRED MASTERSON BURKE MED RES INST
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2007-03-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7102005
• 关键词: blood chemistry; breast neoplasms; caloric dietary content; cancer risk; clinical research; diabetes risk; dietary restriction; geographic difference; human subject; information systems; mathematical model; metabolomics; model design /development; noninsulin dependent diabetes mellitus; patient /disease registry; phlebotomy; plasma; proteomics; serum

DESCRIPTION (provided by applicant): Calorie Restriction (CR) is the most potent, robust, and reproducible known means of extending longevity and decreasing morbidity in lab rodents. Despite 70 years of research, the relevance of this observation for humans remains unknown. Relevance is supported by the established link between obesity and morbidity in humans. Potential linkages are being directly addressed by the NIH-sponsored CALERIE (comprehensive assessment of long-term effects of reducing intake of energy) study. This study will enroll approximately 250 individuals and collect blood samples at 6 time points over 24 months. Our proposed ancillary study has two goals: (A) to support CALERIE by characterizing the plasma metabolome and proteome in these samples; the initial foci being to determine if pre-existing metabolomic profiles, and proteomic profiles being developed in NIH funded studies, enable us to follow CR in people from three geographically distinct sites (thus linking human studies to the rodent literature) and to identify metabolites and pathways of interest, and; (B) to provide data grounding and linking the PI's ongoing studies of the use of metabolomic and proteomic profiles from CR rats to predict future disease risk for type II diabetes and breast cancer with direct data on human caloric intake. Multivariate pattern recognition analysis based on a 93 metabolite profile can distinguish ad libitum fed (AL) and CR rats (100% accuracy in training sets, mean >90% in test sets), and has enabled construction of accurate models of intermediate intakes (r2=0.88) for individual rats. Analytical work has adapted this profile for human plasma. Initial sera proteome profiles also distinguish diet with 100% accuracy. The AIMs are: (1) To determine temporal shifts that occur in the proteome and metabolome at the levels of compounds, pathways, and profiles. Then to use these data to (a) determine quantitative fit to a CR profile pre-, during, and, if possible, post- intervention, and; (b) quantitatively assess movement along a mathematical continuum related to progressive CR in rats. (2) To provide an electronic archive of the metabolomic and proteomic constituents of the blood of participants that could be repeatedly mined for future testing of new hypotheses; (3) To develop mathematical models sensitive to short and long-term low calorie diets in humans to be used in complement with models of disease prediction now being generated in the PIs lab, and; (4) To examine profile changes across the three CALERIE sites to compare and contrast observed changes.

描述（由申请人提供）： 热量限制 (CR) 是已知最有效、最稳健且可重复的延长实验室啮齿动物寿命和降低发病率的方法。尽管进行了 70 年的研究，但这一观察结果与人类的相关性仍然未知。肥胖与人类发病率之间已确定的联系支持了相关性。 NIH 资助的 CALERIE（减少能量摄入的长期影响的综合评估）研究正在直接探讨潜在的联系。这项研究将招募大约 250 名个体，并在 24 个月内的 6 个时间点采集血液样本。我们提出的辅助研究有两个目标：(A) 通过表征这些样本中的血浆代谢组和蛋白质组来支持 CALERIE；最初的重点是确定预先存在的代谢组学谱和 NIH 资助的研究中正在开发的蛋白质组学谱是否使我们能够跟踪来自三个不同地理位置的人的 CR（从而将人类研究与啮齿动物文献联系起来）并识别代谢物和感兴趣的途径，以及； (B) 提供数据基础，并将 PI 正在进行的使用 CR 大鼠的代谢组学和蛋白质组学图谱的研究与人类热量摄入的直接数据联系起来，以预测 II 型糖尿病和乳腺癌的未来疾病风险。基于 93 种代谢物谱的多变量模式识别分析可以区分随意喂养 (AL) 和 CR 大鼠（训练组准确率为 100%，测试组平均值 >90%），并且能够构建准确的中间摄入量模型 (r2 =0.88) 对于个体大鼠。分析工作已将这一特征应用于人血浆。初始血清蛋白质组图谱也能以 100% 的准确度区分饮食。目标是：（1）确定蛋白质组和代谢组在化合物、途径和谱水平上发生的时间变化。然后使用这些数据来 (a) 确定干预前、干预期间以及（如果可能的话）干预后与 CR 概况的定量拟合；以及； (b) 定量评估与大鼠渐进 CR 相关的数学连续体运动。 (2) 提供参与者血液的代谢组学和蛋白质组学成分的电子档案，可以重复挖掘该档案以供未来测试新假设； (3) 开发对人类短期和长期低热量饮食敏感的数学模型，以补充 PI 实验室目前正在生成的疾病预测模型； (4) 检查三个 CALERIE 站点的概况变化，以比较和对比观察到的变化。