High Resolution Plasma Lipidomics in CALERIE

CALERIE 中的高分辨率血浆脂质组学

• 批准号: 8575719
• 负责人: BRUCE S KRISTAL
• 金额: $ 35.28万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8575719
• 关键词: Address; Ancillary Study; Animals; Back; Biological; Biological Markers; Blood; Blood specimen; Caloric Restriction; Data; Data Set; Databases; Detection; Diet; Disease; Early Intervention; Energy Intake; Enrollment; Epidemiologic Studies; Fatty acid glycerol esters; Future; Genetic; Goals; Health; Human; Individual; Insulin Resistance; Intake; Link; Lipids; Longevity; Malnutrition; Mammals; Measures; Methods; Modeling; Morbidity - disease rate; Obesity; Pattern; Plasma; Population Study; Protocols documentation; Rattus; Research; Resolution; Risk; Rodent; Sampling; Series; Shotguns; Signal Transduction; Site; Staging; Time; Triglycerides; United States National Institutes of Health; base; blood lipid; cohort; design; diabetes risk; disorder risk; feeding; liquid chromatography mass spectrometry; malignant breast neoplasm; metabolomics

DESCRIPTION (provided by applicant): Caloric 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 study. This study has enrolled ~220 individuals and collected blood samples at 6 time points over 24 months. Our proposed ancillary study has two goals: (A) to support CALERIE by characterizing the plasma lipidome in these samples by using a newly developed, high resolution liquid chromatography-mass spectrometry-based profiling approach that enables both qualitative and quantitative detection of >425 structurally identified individual lipids in biological samples (e.g, >100 unique triglycerides), and; (ii) to link these data with our existing metabolomics profiling data within the CALERIE cohort and with an equivalent study in rats fed ad libitum or with a series of diets varying in the extent and duration of caloric restriction. The long-range goals of these latter studies are to develop diet-based biomarkers that have utility in human epidemiological studies (for objective recognition of diet) and which predict disease risk in humans (e.g., breast cancer). In support of this proposal, we have shown that CR induces changes in blood lipids in rats, e.g., a reduction in overall circulating triglycerides. Our finer resolution enables us to also show that there are multiple lipid species specific changes, and that these changes differ in both direction and magnitude, even within a single class of lipids such as triglycerides. Furthermore, we have conducted a pilot lipidomics study of ~400 samples drawn from CALERIE, and we show that the signal we can follow is so strong that, even unblinded (and thus including mixed controls and restricted, at a 1:2 ratio), we are able to show the effect on blood lipids with the CALERIE protocol, and we are able to show similar changes in rats and humans. We hypothesize that the proposed high resolution lipidomics study will reveal additional benefits of low calorie diets in humans. The Aims are: Aim 1: To develop, optimize, and validate a defined series of nested plasma lipidomics-based biomarker profiles Aim 2: To determine the similarities, differences, and interactions between the systemic lipidomics profiles and systemic metabolomics patterns Aim 3: To determine the similarities, differences, and interactions between the systemic lipidomics profiles in humans and those in CR animals The proposed study furthers NIH goals of focusing on health and early interventions rather than late stage disease, and is well within our lab's capacity to complete in 2 years.

描述（由申请人提供）：热量限制（CR）是已知的最有效、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 研究正在直接探讨潜在的联系。这项研究招募了约 220 名个体，并在 24 个月内的 6 个时间点采集了血液样本。我们提出的辅助研究有两个目标：(A) 通过使用新开发的、基于高分辨率液相色谱-质谱法的分析方法来表征这些样品中的血浆脂质组，从而支持 CALERIE，该方法能够定性和定量检测 >425 的结构鉴定生物样品中的单个脂质（例如，>100 种独特的甘油三酯），以及； (ii) 将这些数据与我们现有的 CALERIE 队列中的代谢组学分析数据以及对随意喂养或采用一系列不同热量限制程度和持续时间的饮食的大鼠进行的等效研究联系起来。后面这些研究的长期目标是开发基于饮食的生物标志物，这些生物标志物可用于人类流行病学研究（用于客观识别饮食）并预测人类疾病风险（例如乳腺癌）。为了支持这一提议，我们已经证明 CR 会引起大鼠血脂的变化，例如总体循环甘油三酯的降低。我们更精细的分辨率使我们能够证明存在多种脂质种类的特定变化，并且这些变化在方向和幅度上都不同，即使在甘油三酯等单一类别的脂质中也是如此。此外，我们对从 CALERIE 抽取的约 400 个样本进行了试点脂质组学研究，我们表明我们可以跟踪的信号非常强，即使是非盲的（因此包括混合对照和限制性对照，比例为 1:2），我们能够通过 CALERIE 方案显示对血脂的影响，并且我们能够在大鼠和人类中显示类似的变化。我们假设所提出的高分辨率脂质组学研究将揭示低热量饮食对人类的额外好处。目标是： 目标 1：开发、优化和验证一系列明确的基于血浆脂质组学的生物标志物谱 目标 2：确定系统脂质组学谱和系统代谢组学模式之间的相似性、差异和相互作用 目标 3：确定人类和 CR 动物的系统脂质组学特征之间的相似性、差异和相互作用。拟议的研究进一步推进了 NIH 关注健康和早期干预而不是晚期疾病的目标，并且完全符合我们的目标。实验室有能力在2年内完成。