绘制秀丽线虫全脂信息谱图并解析各种脂类在秀丽线虫不同发育阶段和衰老进程中的作用

As aberrant lipid metabolisms are closely associated with many important human diseases including diabetes, neurodegenerative diseases as well as cardiovascular diseases, lipid anomalies could impose considerable threats to human health. As a simple, short- and Due to its simple structure, relatively short lifespan coupled with its genetic tractability, Caenorhabditis elegans is now becoming widely used as a model organism to study pathology of human diseases related to lipid biosynthesis or regulation. Therefore, Caenorhabditis elegans has emerged as a critical model organism for investigation of disease mechanisms related to aging and lipid dysregulation. However, due to the current lack of specific lipidomic platforms for global analysis of the comprehensive lipid profiles of Caenorhabditis elegans, as well as the scarcity of information pertaining to the changes in lipid profiles at the different developmental stages of the organism, establishing a complete network of lipid biosynthesis and metabolism for this organism remains an unyielding task. Therefore, this project aims to systematically characterize the lipid species of Caenorhabditis elegans, and to develop high throughput mass spectrometric methods with high sensitivity and reproducibility tailored for investigating changes in individual lipids during the development and aging of Caenorhabditis elegans. Next, through investigating lipid profiles of relevant mutants (i.e. knockouts, knockdowns, or overexpression) of the critical lipid species associated with the development and aging of Caenorhabditis elegans identified from the global analysis, the precise physiological functions of the identified lipids can be confirmed. The developed lipid mutants and lipidomics platform are also expected to immensely facilitate mechanistic studies related to lipid dysregulation in aging and development.

由于与许多重大人类疾病（包括糖尿病、神经退行性疾病、血管病等）有着非常紧密联系，脂代谢紊乱被认为是当今对人类健康的最大威胁之一。基于其结构简单、生命周期短、遗传易操作性的独特优点，秀丽线虫被广泛应用于研究脂合成及代谢调控异常等相关疾病的致病机理研究。因此，秀丽线虫逐渐成为国际上研究衰老、脂肪积累生理与机制的重要模式生物。然而，由于現今仍然缺乏系统分析秀丽线虫的脂组学方法和线虫在不同发育阶段的全脂信息谱图，以至要建立秀丽线虫的脂合成、代谢调控网络甚为艰巨。因此，本项目将开发用于分析秀丽线虫的各类脂分子的高通量、高灵敏度、高精度、高重复性的现代脂组学方法，绘制线虫在不同发育阶段及衰老进程中的的全脂信息谱图，揭示各类脂分子在不同发育阶段、衰老进程中的关键作用。通过分析与发育、衰老相关的各类脂组分的突变体和过表达体的全脂信息，确证各类脂分子在不同发育阶段、衰老进程中的重要作用并探索脂调控机制。

由于与多种人类重大疾病有着紧密联系，脂代谢紊乱被认为是当今对人类健康的最大威胁之一。基于其结构简单、生命周期短、遗传易操作性的独特优点，秀丽线虫被广泛应用于研究脂合成及代谢调控异常等相关疾病的致病机理研究。然而，由于現今仍然缺乏系统分析秀丽线虫的脂组学方法和线虫在不同发育阶段的全脂信息谱图，以至要建立秀丽线虫的脂合成、代谢调控网络甚为艰巨。因此，本项目主要研究内容是开发用于分析秀丽线虫的各类脂分子的高通量、高灵敏度、高精度、高重复性的现代脂组学方法，绘制线虫在不同发育阶段及衰老进程中的全脂信息谱图。本项目建立了秀丽线虫35类7000多种脂质的分析方法和数据库，并应用建立的分析方法详细分析了线虫生长发育不同阶段的脂质变化，暗示了各类脂分子在不同发育阶段、衰老进程中的关键作用。脂质组学数据结果证明不饱和脂肪酸、脂肪酸链长在线虫的生长、发育和衰老进程可能扮演了重要的作用，发现秀丽线虫持久幼虫通过维持膜磷脂多不饱和脂肪酸含量及控制类花生酸物质的合成延长寿命，研究结果揭示膜脂平衡影响秀丽线虫持久幼虫寿命的新机制。