Arf1介导的脂质代谢维护生物体质量以及其敲除引发的病理机制

糖脂代谢不仅为人体提供物质能量，还直接调节细胞以及机体的功能。然而，我们对糖脂代谢在体内的生物学功能还知之甚少。本实验室首次发现Arf1介导的脂质代谢对于生物体质量的维持极为重要。Arf1在干细胞和神经元中的敲除引发系统性衰退的级联反应，包括脂滴、过氧化物脂质的形成和扩散，以及全身性的炎症和免疫反应。在正常生理情况下，该级联反应能够导致神经退行性疾病和干细胞衰老死亡；而在癌症中，该级联反应导致系统性的抗肿瘤免疫反应。我们的模型能很好地将脂质代谢相关的生化知识与体内的生物学和病理学功能联系起来。在本项目中，我们计划解决以下三个问题：（1）探究Arf1介导的脂质代谢对干细胞质量维持的具体机制；（2）探究在Arf1敲除的肿瘤干细胞中，脂滴和过氧化物脂质形成和转移的机制；（3）探究过氧化物脂质促进抗肿瘤免疫的机制。本项目的实施将为神经退行性疾病、以及癌症的诊断和治疗提供重要的理论基础和指导意义。

Glycolipid metabolism not only provides the body’s energy and material needs but also directly regulates cellular and organismal biological functions. However, our understanding of the biological functions of glycolipid metabolism in vivo is still scarce. Our laboratory recently found that the Arf1-mediated lipid metabolism plays an important role in the organismal quality control. Its ablation in stem cells and neurons resulted in systemic deterioration and aging, including formation and transfer of lipid droplets and peroxided lipids as well as activation of inflammation and immune response. The deteriorating cascade will promote neurodegeneration and stem cell aging in physiological conditions as well as CSC death and anti-tumor immunity in cancers. Our study provides an ideal model to connect the biochemical knowledge of the lipid metabolism to biological or pathological functions in vivo. In this proposal, we will use both mouse and Drosophila models to explore the molecular mechanism, by which the Arf1 pathway sustains stem cell quality during homeostasis and Arf1-ablation in CSCs promotes formation and transfer of LDs and peroxided lipids that further activates anti-tumor immune responses in cancers. The outcome of this study will provide important theoretical basis and guiding significance for the diagnosis and treatment of neurodegenerative diseases and cancer.