星形胶质细胞hnRNPA1选择性装载microRNA-34a入外泌体介导糖尿病海马神经元退行性变的作用及机制研究

从细胞间通讯的角度，探索糖尿病星形胶质细胞功能异常对神经元的影响有助于阐述糖尿病认知障碍的发病机制。外泌体可通过传递其装载的miRNA介导细胞间通讯；hnRNPA1能与miR-34a相互作用。我们发现：高糖培养的星形胶质细胞分泌的外泌体能加速海马神经元退行性变，其作用可被anti-miR-34a取消；糖尿病大鼠星形胶质细胞胞核及胞浆hnRNPA1表达增加；干扰hnRNPA1逆转高糖诱导的miR-34a在外泌体与供体细胞中比值的增加。由此推测：高糖通过促hnRNPA1表达而装载miR-34a入外泌体，并将miR-34a传递给神经元而加速其退行性变。本项目在验证该假设的基础上，研究hnRNPA1与miR-34a相互作用的结构基础，并从胰岛素受体类型转换的角度探讨hnRNPA1启动自身滞留胞浆及胞核内高表达的正反馈机制，揭示miR-34a被装载入外泌体的始动环节；为防治糖尿病认知障碍提供新靶点。

From the perspective of cell-to-cell communication, exploring the effect of astrocyte dysfunction on neurons under diabetic condition helps to elucidate the pathogenesis of diabetic cognitive impairment. Exosomes can mediate cell-to-cell communication by delivering their loaded miRNAs. Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) can interact with microRNA-34a (miR-34a). We found that 1) exosomes secreted by high glucose-treated astrocytes accelerated the degeneration of hippocampal neurons, which was abolished by anti-miR-34a; 2) the expression of hnRNPA1 was increased in the nucleus and cytoplasm of astrocytes of diabetic rats; 3) the increased exosomes/cells ratio of miR-34a induced by high glucose could be reversed by the depletion of hnRNPA1. We speculate that: under high glucose conditions, the overexpression of hnRNPA1 in astrocytes promotes the packaging of miR-34a into exosomes，and then the exosomes transmits miR-34a to neurons, resulting in the acceleration of neurodegeneration. Based on the validation of this hypothesis, this project will investigate the structural basis of the interaction between hnRNPA1 and miR-34a, explore how the overexpression of hnRNPA1 initiates the positive feedback mechanism involving the cytoplasmic retention and high expression in nucleus, and their association with insulin receptor type conversion. The study will reveal the initial event of the packaging of miR-34a into exosomes and provide a new target for the prevention and treatment of diabetes cognitive disorders.