琥珀酸/GPR91调控PKCδ/Akt1信号通路参与深低温低流量后脑缺血再灌注损伤的机制研究

深低温低流量（DHLF）后脑缺血再灌注损伤（IRI）是目前复杂先心病体外循环术后亟待解决的重要并发症。GPR91广泛存在于心脑等组织，能与琥珀酸特异性结合发挥作用，研究表明琥珀酸/GPR91参与心肌IRI。本课题组在DHLF模型中发现琥珀酸/GPR91表达明显增加，提示其可能参与了DHLF后脑IRI。PKCδ和Akt1是DHLF后脑IRI的重要分子，我们发现，PKCδ能促进脑损伤加重，而Akt1具有脑保护作用，过表达PKCδ后能抑制Akt1表达并加重神经元损伤。此外研究发现GPR91可以激活PKCδ的表达而加重IRI。因此我们推测，琥珀酸/GPR91通过调控PKCδ/Akt1参与DHLF后脑IRI的发生发展。为验证此假说，我们采用过表达与沉默策略，结合免疫共沉淀等技术，验证GPR91对PKCδ/Akt1的调控关系，阐明其在DHLF后脑IRI中的作用，为DHLF后脑保护策略提供新的理论依据。

Cerebral ischemia-reperfusion injury (IRI) after deep hypothermia low flow (DHLF) is an urgent issue for complex congenital heart disease operation. GPR91, specifically binding with succinate, is widely found in heart and brain. Studies have shown that succinate/GPR91 play a role in myocardial IRI. We found that the expression of succinate/GPR91 was significantly increased after DHLF, suggesting that they may be involved in cerebral IRI after DHLF. PKCδ and Akt1 play an important role in cerebral IRI after DHLF and we found that PKCδ could aggravate cerebral IRI, while Akt1 have a protective effect, and overexpression of PKCδ decreased the expression of Akt1 and aggravated cerebral IRI. Additionally, studies showed that GPR91 increased the expression of PKCδ and aggravated IRI. Accordingly, we hypothesized that succinate/GPR91 regulated PKCδ/Akt1 signaling pathway in cerebral IRI after DHLF. We used overexpression and silencing strategies, combined with co-immunoprecipitation technologies to verify the relationship between GPR91 and GPR91, which could explain the mechanism of cerebral IRI after DHLF. The solution of this scientific problem will provide a new theoretical basis for cerebral protection strategy after DHLF.