NDRG2调控“星形胶质-血管”网络可塑性在SAH后神经损伤中的作用及机制研究

Delayed brain injury (DBI) is a main cause of the high mortality and disability in subarachnoid hemorrhage (SAH) patients. However, the underlying mechanism is still unclear. The essential pathology of SAH is the dysfunction of “neuron-astrocyte-vessel” network, in which astrocyte plays a vital role in the cross-talk. NDRG2 is a new-found biomarker of astrocyte. Our previous studies strongly suggest NDRG2 acts as a key factor in the “astrocyte-vessle” dysfunction after SAH through regulating astrocytic plasticity via the downstream signalings. In the present study, with the help of NDRG2 gene knockout animal and SAH model, we conduct the mode of cellular mechanism study combining with animal functional verification, and the research approach of pharmacological intervention combining with gene regulation targeting on astrocyte. We are aiming to define the role and mechanism that NDRG2 participates in the DBI after SAH through regulating astrocytic plasticity, and establish an effective intervention strategy for SAH treatment targeting NDRG2. Thus, our findings will contribute to the comprehensive understanding of the pathological mechanism of SAH, and provide theoretical basis and experimental evidence for clinical SAH treatment.

迟发性脑损伤是蛛网膜下腔出血（SAH）残死率居高不下的重要原因，但目前机制不明确。SAH后的病理改变实质上是“神经元-星形胶质-血管”网络调控的紊乱，处于中心环节的星型胶质细胞发挥重要的调节作用。NDRG2是新近发现的星形胶质细胞特异性表达的应激调控分子，我们前期研究高度提示，NDRG2通过调控星形胶质细胞可塑性，并介导下游信号在SAH后迟发性“胶质-血管”结构破坏和功能障碍中发挥关键作用。本课题拟以星形胶质细胞为切入点，采用多种NDRG2基因模式动物及SAH动物模型，采取细胞机理探讨与动物功能验证相结合的研究模式、以药理学干预与基因调控相结合的研究手段，明确NDRG2调控星形胶质细胞可塑性参与SAH后迟发性脑损伤调节的作用及分子机制，建立靶向NDRG2的SAH干预策略，为临床全面认识SAH的病理损伤机制及治疗提供理论基础和实验依据。

迟发性脑损伤是蛛网膜下腔出血（SAH）残死率居高不下的重要原因，但目前机制不明确。SAH后的病理改变实质上是“神经元-星形胶质-血管”网络调控的紊乱，处于中心环节的星型胶质细胞发挥重要的调节作用。本课题将深入研究星形胶质细胞特异性应激调控分子NDRG2通过调控星形胶质细胞可塑性介导SAH后神经-血管损害的作用机制，最终建立靶向NDRG2的SAH后神经保护的干预策略。明确NDRG2表达增高与SAH后神经损伤呈正相关，抑制NDRG2表达能够减轻SAH后的星形胶质细胞活化、炎症反应及血脑屏障破坏。证实了SAH后星形胶质细胞中NDRG2和GLT1的相反表达模式，NDRG2可能通过与NF-κB p65结合来抑制GLT1基因的转录，进而抑制星形胶质细胞的谷氨酸摄取能力，诱发神经元死亡。证实反应性星形胶质细胞NDRG2通过与蛋白磷酸酶PPM1A结合，抑制PPM1A核转位对Smad2/3的去磷酸化，维持了Smad2/3的转录活性，促进了MMP-9的表达，加重SAH后BBB的破坏。通过构建工程化模拟NDRG2-PPM1A结合域的多肽干预，可以抑制MMP-9的表达，进而保护BBB，减轻SAH后继发性脑水肿。本研究从星形胶质细胞的角度部分揭示了SAH后神经-血管损伤中的作用及机制，并开发了靶向NDRG2抑制MMP-9的多肽，初步在动物模型中证实其对SAH后BBB的保护作用，为SAH后的治疗提供了新思路和新方法。