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）是已知延长实验室啮齿动物寿命和降低发病率的最有效、最稳健、最可重复的方法。尽管经过70年的研究，这一观察结果对人类的相关性仍然未知。相关性得到了人类肥胖和发病率之间既定联系的支持。NIH赞助的CALERIE研究直接解决了潜在的联系。本研究入组了约220例受试者，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-质谱的分析方法表征这些样品中的血浆脂质组来支持CALERIE，该方法能够定性和定量检测生物样品中>425种结构鉴定的单个脂质（例如，>100种独特的甘油三酯），和;（ii）将这些数据与CALERIE组群中我们现有的代谢组学分析数据以及与在随意喂养或具有一系列在热量限制的程度和持续时间方面变化的饮食的大鼠中的等效研究相关联。这些后者研究的长期目标是开发基于饮食的生物标志物，其在人类流行病学研究中具有实用性（用于饮食的客观识别）并且预测人类的疾病风险（例如，乳腺癌）。为了支持这一提议，我们已经证明CR诱导大鼠血脂的变化，例如，降低总循环甘油三酯。我们更精细的分辨率也使我们能够表明存在多种脂质物种特异性变化，并且这些变化在方向和幅度上都不同，即使在单一类别的脂质（如甘油三酯）中也是如此。此外，我们对从CALERIE提取的约400个样本进行了一项初步脂质组学研究，我们表明，我们可以遵循的信号非常强，即使揭盲（因此包括混合对照和限制，比例为1：2），我们也能够显示CALERIE方案对血脂的影响，并且我们能够在大鼠和人类中显示类似的变化。我们假设，拟议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益处。目标是：目标1：开发、优化和验证一系列确定的基于嵌套血浆脂质组学的生物标志物谱目标2：确定全身脂质组学谱和全身代谢组学模式之间的相似性、差异性和相互作用目标3：为了确定相似点，不同点，以及人类和CR动物的全身脂质组学特征之间的相互作用。早期干预而不是晚期疾病，这完全在我们实验室的能力范围内，可以在2年内完成。