高尔基体脂质代谢重塑及其关键限速酶在可卡因成瘾中的作用及其分子机制

脂质分子在突触重塑过程中为突触新生与生长发挥重要作用，但在药物成瘾过程中，脂质分子的代谢生成及参与膜重塑的过程并不清楚。我们前期发现，可卡因重塑小鼠伏隔核脂质代谢，尤其是高尔基体特异性代谢生成的葡萄糖神经酰胺（GlcCer）水平显著增加，GlcCer生成的关键限速酶——葡萄糖神经酰胺合成酶（GCS）表达也显著升高。由于GCS特异性表达于高尔基体，提示可卡因诱导的脂质代谢重塑发生在不同于常规脂质代谢的细胞器（内质网、线粒体）。本课题系统研究可卡因成瘾形成过程中，高尔基体GCS作为“脂质代谢引擎”调节伏隔核脂质代谢与可卡因成瘾行为的生物学效应及其机制，聚焦脂质分子GlcCer在神经元亚细胞结构的代谢合成、转运、轴突转运以及参与膜重塑的分子过程，从细胞轴突、三维超微结构重构、长时程增强等多角度深入研究GlcCer如何参与突触可塑性。预期将阐明高尔基体脂质代谢在参与成瘾表型及突触可塑性的分子机制。

Neuronal lipids play a key role in synaptic renewal and growth during synaptic remodeling. However, the regulatory mechanisms of lipid molecules in lipid metabolism, transport and membrane remodeling are not clear. We previously found that cocaine can remodel lipid metabolism in the nucleus accumbens of mice, especially the glucosylceramide（GlcCer）level was significantly elevated. Furthermore, by PCR screening the transcriptional level of gene related lipid metabolism, we found that the expression of glucosylceramide synthase (GCS), the key rate-limiting enzyme of GlcCer production, was significantly increased. As GCS is specifically expressed in the Golgi apparatus, it is suggested that cocaine-induced lipid metabolism remodeling may occur in organelles that are different from other conventional ones (such as endoplasmic reticulum and mitochondria). In this study, we will investigate the molecular mechanism of GCS as a "molecular engine" of lipid metabolism, including lipid metabolism remodeling, dynamic transport of lipid molecules, and participation in the synaptic plasticity. We will focus on the GlcCer, a key lipid molecule, including its intracellular transport, spatial distribution within subcellular structure, involvement in membrane remodeling and synaptic plasticity. This study aims to elucidate the molecular mechanism of lipid metabolism mediated by Golgi apparatus and its role in regulating drug addiction and synaptic plasticity.