lncRNA GAS5 / miRNA-21 crosstalk: 提高深低温停循环脑缺血耐受的新靶点

Deep hypothermia circulatory arrest (DHCA) is required for the repair of aortic arch lesions and complex pediatric congenital cardiac diseases. Cerebral injury is one of the main complications after DHCA. Cerebral infarction and cerebrovascular disease are risk factors to aggravate cerebral injury induced by DHCA. Cellular energy metabolism impairment, oxidative stress and neuronal apoptosis induced by mitochondrial damage play dramatic roles in the cerebral injury induced by DHCA. lncRNA and miRNA are important control mechanisms after transcription, but little is known about functions of lncRNA and miRNA in the pathology of ischemic cerebral injury. Both lncRNA GAS5 and miRNA-21 are expressed in the brain. miRNA-21 is related to the mitochondrial function and neuronal apoptosis. lncRNA GAS5 contributes to the proliferation and apoptosis of glioma cells. According to bioinformatics-based databases, miRNA-21 is indicated to be a possible target of lncRNA GAS5. Using the DHCA models of normal rats and rats with cerebral infarction and cerebrovascular stenosis, the effects of targeted regulation of lncRNA GAS5/miRNA-21 on cellular energy metabolism, mitochondrial dynamics, mitophagy, neuronal apoptosis and neurologic functions will be evaluated. The possibility of increase of the temperature and prolongation of the duration of DHCA will also be investigated. The final objective of the current grant is to explore a novel molecular target to improve the cerebral tolerance against ischemia injury induced by DHCA.

深低温停循环(DHCA)是主动脉弓以及复杂先心病手术必须的辅助措施。脑损伤是DHCA的严重并发症之一，脑梗塞及脑血管病变是叠加DHCA脑损伤的重要危险因素。线粒体损伤导致的能量代谢障碍、氧化应激以及神经元凋亡是DHCA脑损伤的主要机制。作为转录后调控分子，LncRNA和miRNA在DHCA脑损伤中的作用知之甚少。lncRNA GAS5和miRNA-21均在脑中表达。miRNA-21与线粒体功能和细胞凋亡密切相关。lncRNA GAS5亦参与神经胶质瘤细胞的增殖与凋亡。生物信息学预测miRNA-21为lncRNA GAS5可能的靶分子。本课题拟利用已建立的正常、脑梗塞及脑血管狭窄大鼠DHCA模型，系统评价靶向调控lncRNA GAS5/miRNA-21对神经元能量代谢、线粒体功能、线粒体自噬、凋亡及脑神经功能的影响，探讨提高DHCA温度和延长时限的可能，为临床DHCA脑保护提供新的分子靶点。

深低温停循环(DHCA)是主动脉弓以及复杂先心病手术必须的辅助措施。脑损伤是DHCA的严重并发症之一，脑梗塞及脑血管病变是叠加DHCA脑损伤的重要危险因素。线粒体损伤导致的能量代谢障碍、氧化应激以及神经元凋亡是DHCA脑损伤的主要机制。作为转录后调控分子，LncRNA和miRNA在DHCA脑损伤中的作用知之甚少。本课题通过大鼠DHCA模型发现lncRNA GAS5在DHCA后表达明显升高，作为其靶分子之一的miRNA-23a表达降低，并且抑制lncRNA GAS5的表达升高后可以有效减少神经元凋亡、调节线粒体功能最终减轻DHCA后脑损伤；并且调控miR-494的表达也可达到类似的作用。均在脑中表达。miRNA-23a与线粒体功能和细胞凋亡密切相关。后续研究更加证实DHCA过程可以导致众多non-coding RNA表达异常，并尝试探究脑梗塞后DHCA的可行性及相关机制。本课题成功建立了lncRNA GAS5/miRNA-23a信号通路，成功通过调节lncRNA及miRNA对神经元能量代谢、线粒体功能、凋亡及脑神经功能产生影响，有效减轻DHCA后脑损伤，为临床DHCA脑保护提供新的分子靶点及治疗方向。