环状RNAcircRIMS2通过BDNF介导的神经保护作用参与有氧运动改善血管性认知功能障碍的机制研究

Aerobic exercise can improve the cognitive function of patients with vascular cognitive impairment(VCI), and its mechanism provides an important basis for the treatment of VCI. Our team has confirmed that aerobic exercise improves brain-derived neurotrophic factors(BDNF) and mitigates VCI progress, which can be achieved by increasing annular RNA circRIMS2 and changing the level of miR-186, but the mechanism is unclear. On the basis of the previous studies and the VCI patient and mouse model, our group willdo the following:(1) Test the level of circRIMS2, miR-186 and BDNF in serum and its correlation with cognitive function and neuroimaging; (2) Explore the regulating mechanism of mircRIMS 2 on the expression of miR-186 mediated by BDNF at cellular level; (3)Study the changes of expression of BDNF and miR-186 in hippocampus to clearify the effects of circRIMS2/miR-186/BDNF pathway on neural stem cell differentiation and neuronal apoptosis after aerobic exercise in VCI rats.This study will clarify the mechanism of circRIMS2 in aerobic exercise to improve VCI, providing theoretical support for early prevention and diagnosis of VCI.

有氧运动有效改善血管性认知功能障碍（VCI）患者认知功能，探究其机制可为该病治疗提供重要依据。课题组已证实有氧运动提高脑源性神经营养因子（BDNF），缓解VCI进展，其作用通过上调环状RNAcircRIMS2，改变miR-186水平实现，但具体机制不明。本申请在前期研究基础上，借助VCI患者及小鼠模型，进一步研究：（1）血清circRIMS2、miR-186、BDNF表达水平，明确其与认知功能及神经影像相关性；（2）从细胞水平探究circRIMS2对BDNF介导miR-186表达的调节机制；（3）研究有氧运动上调VCI大鼠海马circRIMS2后，BDNF及miR-186表达的变化，明确有氧运动干预的circRIMS2/miR-186/BDNF通路对神经干细胞分化和神经元细胞凋亡的影响。本研究将明确circRIMS2在有氧运动改善VCI中的作用机制，为VCI的早期防治和诊断提供理论支撑。

本项目主要探究有氧运动通过影响海马神经元细胞凋亡，改善血管性认知功能障碍（VCI）的作用机制。我们的前期研究已证实有氧运动在改善VCI中发挥重要作用。本研究发现miR-186，lncRNA TUG1在VCI 患者中表达升高，circRIMS2及BDNF表达降低；在小鼠VCI模型中同样发现circRIMS2表达降低，而有氧运动可显著上调circRIMS2水平。体外研究表明，circRIMS2和BDNF在氧糖剥夺（OGD）处理的细胞中表达水平降低，miR-186，lncRNA TUG1表达增加，细胞凋亡增加，而过表达circRIMS2或抑制lncRNA TUG1可减少细胞凋亡。此外，我们还证实了circRIMS2与miR-186，miR-186与BDNF，lncRNA TUG1与BDNF的结合关系，在此研究基础上，我们进一步发现circRIMS2通过miR-186/BDNF通路，lncRNA TUG1通过调控BDNF抑制海马神经元细胞凋亡。进一步的体内研究证明有氧运动缩短了小鼠到达Morris水迷宫平台的平均时间，提高了circRIMS2和BDNF的表达水平，降低了miR-186，lncRNA TUG1的表达，抑制了神经元凋亡。总之，我们的研究发现在VCI模型中circRIMS2的表达水平降低，lncRNA TUG1表达水平升高，而有氧运动可以提高circRIMS2的表达水平，下调miR-186 和lncRNA TUG1的水平，导致BDNF水平升高，进一步减少海马神经元凋亡，从而抑制VCI病理发展，改善认知功能。