细胞能量代谢途径决定免疫细胞的活化，但是尚不清楚调控能量代谢途径重编码的机制。胞内脂质的过度积累所导致的巨噬细胞（MФ）泡沫化损坏了MФ的免疫功能；脂滴和线粒体是泡沫细胞中最丰富的细胞器；细胞器之间的通讯决定细胞表型。申请人的前期研究表明：线粒体的融合和氧化磷酸化在泡沫MФ中增强；抑制线粒体融合蛋白Mfn1促进了MФ泡沫化并加强了炎症反应。由此，申请人提出假设：在泡沫细胞中，脂滴将脂质过多的信号通过其膜上的蛋白传递给线粒体，促使线粒体融合以增强氧化磷酸化代谢脂肪酸，这种MФ的代偿方式受损促进了动脉粥样硬化的发展。本课题首先拟利用蛋白质组学分析泡沫MФ中脂滴的组成，然后利用RNAi文库筛选促进线粒体氧化磷酸化的脂滴蛋白，随后研究脂滴蛋白在MФ及动脉粥样硬化中的功能，并确定这一蛋白介导脂滴与线粒体通讯的分子机制。本课题有助于了解MФ代谢途径重构的调控机制，探索脂滴与线粒体互作的分子机制及功能。

Cellular energy metabolism determines the activation fate of immune cells. However, the mechanisms by which cellular energy metabolic pathways are reprogrammed during macrophage activation are still unclear. Foamy macrophage formation caused by lipid overload impairs the immune function of macrophages, and is the main pathologic factor of atherosclerosis. Lipid droplet (LD) and mitochondria are the main organelles in foamy macrophages, while interactions between organelles are vital for cell function. Our preliminary data showed that mitochondrial oxidative phosphorylation is enhanced in foamy macrophages, associated with elongated mitochondria. Of note, the expression of Mitofusin 1 (Mfn1), that is a mediator of mitochondrial fusion, was upregulated in atherosclerotic aortas from Apoe-/- mice fed on high fat diet for 12 weeks, and then was downregulated in those for 24 weeks. Inhibition of Mfn1 enhanced foam cell formation and increased the expression of the inflammatory mediators in macrophages. Therefore, we assumed that the crosstalk between lipid droplet and mitochondria may cause mitochondrial fusion, which is the compensatory mechanism for macrophages to get rid of overloaded lipid; but this is impaired in advanced atherosclerosis. To verify this hypothesis, we will firstly perform proteome analysis of LD isolated from foamy macrophages, followed by RNAi library screening to select the LD proteins responsible for mitochondrial oxidative phosphorylation and we will name this/these protein(s) as LD-mito protein(s). Secondly we will investigate the function of LD-mito protein(s) in macrophages and atherosclerosis. At last, we will find out the molecular mechanism underlying the communication between LD and mitochondria mediated by LD-mito protein(s). Our study will deep the understanding of metabolic reprogramming in foamy macrophages, and find out the novel mechanism underlying foam cell formation at the level of organelles.