通过受激拉曼散射（SRS）成像研究新基因elid-1调控脂肪分解的分子机制

我国肥胖问题日益严重，对国民健康影响重大。研究脂肪分解的调控机制是解决肥胖问题的关键。由于脂类难以用普通光学显微镜观察以及脂代谢的复杂性，对其研究很具挑战性。受激拉曼散射（SRS）显微镜能捕捉脂类碳氢键的拉曼信号来对脂类进行非标记化学成像并定量，是脂类研究的强大工具。基于SRS,我们还开发了对脂类的含量、分布、成分和动态进行成像的方法。本项目利用自己搭建的SRS显微镜，并以秀丽线虫为模型，通过高通量遗传筛选得到一系列脂代谢异常的突变体，并精细定位克隆了调控脂肪分解的新基因elid-1，还借助SRS成像检测了脂肪含量与分布、脂滴大小与数目、脂肪合成与分解速率、饥饿下脂肪分解情况等表型。我们将进一步用转录组和代谢组分析、遗传筛选抑制子等多种手段深入研究elid-1调控脂肪分解的分子机制。保守基因elid-1的研究成果可以扩展到高等生物中，将有助于寻找控制肥胖的方法和药物，解决肥胖问题。

Obesity has become a real threat in China, resulting serious health problems. Studying mechanisms of lipid catabolism regulation holds the key to solve obesity threat. However, studying lipid is challenging due to its invisibility under regular optical microscopes and the complexity of its metabolism. By capturing Raman scattering signal of CH2 bonds in lipids, stimulated Raman scattering (SRS) microscopy can label-free chemically image and quantify lipid molecules in vivo. It is a powerful tool for lipid research. Based on SRS microscopy, we developed a series of novel methods to image lipid level, distribution, composition and dynamics. In this project, we take advantage of our newly home-built SRS system and together with C.elegans as a model to efficiently study lipid metabolism. We conducted the first high-throughput forward genetic screen using SRS microscopy and systematically identified many C. elegans mutants with altered lipid profile phenotypes. Using whole genome sequencing, we further mapped and cloned a novel gene named elid-1 that regulates lipid catabolism. We also characterized its lipid phenotypes such as lipid level, distribution, lipid droplet size and number, fat synthesis and mobilization rates, and lipid catabolism upon fasting using SRS microscopy. We will further study its novel molecular regulatory mechanisms of lipid catabolism using various approaches, such as transcriptome and metabolome analysis, and genetic suppressor screens. Our mechanistic characterization of this conserved gene will advance our understanding of lipid metabolic regulation in higher organisms, and shed new light on the control and treatment of obesity.