循环外泌体启动血—脑通讯在有氧运动改善2型糖尿病认知障碍中的精准调节作用

T2DM是认知障碍及痴呆发病的独立危险因素，中枢IR是核心机制。有氧运动可改善认知功能，机理未明。外泌体可携带ncRNA跨越血脑屏障定位于脑实质，已成为神经系统药物靶向治疗的重要载体。研究发现，Malat1与miR-382-3p在T2DM患者血循环中特异表达，两者之间的互作关系是有氧运动改善小鼠主动脉内皮IR的重要机制。生信分析表明miR-382-3p与脑内主管能量代谢和认知功能的BDNF具有结合位点。在此基础上，课题组提出假说：有氧运动是否通过激活循环外泌体表达，启动血—脑通讯，将Malat1/miR-382-3p从外周循环转运至特定的脑实质细胞，上调BDNF表达，减轻中枢IR，改善认知功能。本研究拟通过临床、动物、细胞三部分实验观察外泌体携带ncRNA转运的全过程，采用功能缺失或过表达研究阐明Malat1/miR-382-3p/BDNF在有氧运动改善T2DM认知障碍中的靶向调节作用。

T2DM is an independent risk factor for cognitive impairment and dementia, the central IR is the core mechanism.Aerobic exercise has been shown to improve cognitive function, the mechanism is unknown.Exosomes, which can carry ncRNA across the blood-brain barrier and locate in the brain parenchyma, have become an important carrier for drug targeting therapy of the nervous system.Previous studies have found that Malat1 and miR-382-3p are specifically expressed in the blood circulation of T2DM patients, the interaction between them is an important mechanism for aerobic exercise to improve aortic endothelial IR in mice.Bioinformatics analysis showed that miR-382-3p had binding sites with BDNF, which is responsible for energy metabolism and cognitive function in the brain.On this basis, the research group proposed a hypothesis: whether aerobic exercise can transfer Malat1/miR-382-3p from peripheral circulation to specific brain parenchyma cells by activating the expression of exosomes in blood circulation and provoking the blood-brain communication,then regulate the expression of BDNF in brain, eventually reduce central IR and improve cognitive function.This study intends to observe the whole process of exosomes carrying ncRNAs across the blood-brain barrier through clinical, animal and cell experiments, and clarify the targeted regulatory role of Malat1/miR-382-3p/BDNF in the improvement of T2DM cognitive impairment by aerobic exercise through the study of functional deficiency or overexpression.