自噬受阻引发小胶质细胞过度活化参与应激性高血压调控的机制研究

The occurrence and progression of stree-induced hypertension (SIH) are closely related to sympathetic hyperactivity. The previous studies have demonstrated that both microglial hyperactivation and ACE2/AT1 homeostasis imbalance in rostral ventrolateral medulla (RVLM) contribute to the progression of SIH. However, the relationship between microglial hyperactivation and ACE2/AT1 homeostasis imbalance is unclear. Recently,our in vivo experiments show that microglia is activated and microglial autophagosome is accumulated in the RVLM of SIH rats. In addition, our in vitro experiments show that the expression of autophagy related protein LC3-II is elevated and the activity of lysosome is also significantly decreased in the activated microglia. There results lead us to speculate that autophagy obstruction may induce microglia hyperactivation and then participation in regulating SIH. In this study, we will conduct a series of in vivo and in vitro experiments, including gene knock out, morphology, patch, molecular biology, to investigate this hypothesis. The major research contents would include: (1) the changes of autophagy functions in activated microglia of SIH rat; (2) the relationship between the microglia hyperactivation and the changes of autophagy functions; (3) the mechanism of activated microglia-induced ACE2/AT1 homeostasis imbalance on sympathetic activity. This work will not only reveal the mechanism of microglia hyperactivation in RVLM of SIH rat and the effects of microglia on regulating the sympathetic activity, but may also identify new drug targets for SIH therapy.

应激性高血压（SIH）发生、发展与交感神经活动亢进紧密相关。现有研究结果提示：SIH大鼠延髓头端腹外侧区（RVLM）小胶质细胞过度活化、ACE2/AT1稳态失衡，但两者之间的关联尚不清楚。我们近期研究发现：SIH大鼠RVLM小胶质细胞活化、且细胞内自噬小体堆积；离体活化的小胶质细胞自噬相关蛋白LC3-II增多但溶酶体活性降低。基于此我们推测“小胶质细胞自噬受阻可能是引发细胞过度活化进而参与SIH调控的关键因素”。本课题拟在前期研究基础上，结合在体、离体实验，采用基因敲除、形态学、膜片钳、分子生物学等技术，深入研究：（1）SIH大鼠活化的小胶质细胞中自噬功能的改变；（2）小胶质细胞自噬功能改变与其过度活化的关系；（3）活化的小胶质细胞诱导ACE2/AT1稳态失衡影响交感活动的机制。本研究将开拓性地探索SIH大鼠RVLM小胶质细胞过度活化机制及其调控交感活动的机理，以期为SIH治疗提供新靶点。

脑特定核团调控应激性高血压是防治此类疾病的主要手段之一。延髓头端腹外侧区与下丘脑室旁核在调控应激性高血压发生发展过程中起重要作用，本项目较为系统深入地研究了脑内不同类型细胞“串话”、细胞自噬参与高血压调节的分子及神经机制。研究结果发现并证实：1.应激性高血压诱使延髓头端腹外侧区与下丘脑室旁核小胶质细胞过度激活；2.过度激活的小胶质细胞诱发周边神经元自噬功能障碍，脑内神经元活动亢进进而引起外周交感超兴奋； 3. 伴随高血压病理进程的加剧，脑内小胶质细胞趋向M1型转换，向M1型转换过程主要由UCP2信号通路依赖的线粒体氧化损伤所介导；4. 外周T淋巴细胞“穿越”血脑屏障侵入脑内，呈现Th17/Treg失衡（主要由M1小胶质细胞释放的炎症细胞因子诱导T淋巴细胞向Th17细胞分化所致）；5. 脑内神经元胞膜上的离子通道Nav1.6与Kv10.2均可通过调节囊泡谷氨酸转运蛋白影响外周交感兴奋进而调节血压变化。脑内M1型小胶质细胞与Th17淋巴细胞协同影响外周交感神经紧张性，加剧高血压疾病的发展。这些研究成果不仅丰富了神经调节血压稳态的理论，而且揭示了小胶质细胞互作神经元/T淋巴细胞的机制，更为高血压的临床治疗提供了新的手段与新的策略。在本项目的资助下，已发表SCI科研论文12篇，获授权专利1项。

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