High Resolution Plasma Lipidomics in CALERIE

描述（由申请人提供）：热量限制（CR）是已知的最有效、最稳健、最可重复的延长实验室啮齿动物寿命和降低发病率的方法。尽管经过了70年的研究，这一观察结果与人类的相关性仍然未知。人类肥胖与发病率之间已建立的联系支持了相关性。美国国立卫生研究院赞助的CALERIE研究直接解决了潜在的联系。本研究共招募了约220人，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)通过使用新开发的高分辨率液相色谱-质谱分析方法来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结构确定的单个脂质（例如，>100独特的甘油三酯）；（ii）将这些数据与我们在CALERIE队列中现有的代谢组学分析数据以及在自由喂养或在热量限制程度和持续时间上不同的一系列饮食中对大鼠进行的等效研究联系起来。这些后一项研究的长期目标是开发基于饮食的生物标志物，这些生物标志物在人类流行病学研究中具有实用性（用于客观识别饮食），并预测人类的疾病风险（例如乳腺癌）。为了支持这一建议，我们已经证明CR诱导大鼠血脂的变化，例如，减少总循环甘油三酯。我们更精细的分辨率也使我们能够显示出多种脂类的特定变化，并且这些变化在方向和幅度上都不同，甚至在单一类脂类（如甘油三酯）中也是如此。此外，我们已经对从CALERIE提取的约400个样本进行了试点脂质组学研究，我们表明，我们可以遵循的信号非常强，即使是非盲法（因此包括混合对照和限制，以1:2的比例），我们也能够显示CALERIE方案对血脂的影响，我们能够显示大鼠和人类的类似变化。我们假设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益处。目标是：目标1：开发、优化和验证一系列定义的基于血浆脂质组学的嵌套生物标志物谱；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、差异性和相互作用；目标3：为了确定人类和CR动物的系统脂质组学特征之间的相似性、差异性和相互作用，拟议的研究进一步推动了NIH关注健康和早期干预而不是晚期疾病的目标，并且在我们实验室的能力范围内完成2年。

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.