糖尿病是缺血性脑损伤一个高危因素，但是临床中能减少糖尿病患者缺血性脑损伤的治疗措施很少。我们的前期研究表明抑制Rac1活性在治疗糖尿病缺血性脑损伤中发挥关键作用。抑制Rac1活性也可以促进线粒体自噬而发挥抗缺血性脑损伤作用。前期研究还显示抑制Rac1后，引发线粒体内LncRNA-MEG3水平上调，且LncRNA-MEG3介导了抑制Rac1活性的神经保护作用。此外，明确了与LncRNA-MEG3互作的线粒体蛋白为FUNDC1，而FUNDC1是调控线粒体自噬的关键因子。因此Rac1-LncRNA-MEG3通路可能与FUNDC1相互作用调控线粒体自噬，但具体机制目前尚不清楚。故本项目的目标是阐明LncRNA-MEG3参与调控糖尿病缺血性脑损伤后线粒体自噬以及Rac1-LncRNA-MEG3与FUNDC1相互作用的分子机制。为临床糖尿病缺血性脑损伤的治疗提供新的靶点和理论依据。

Diabetes mellitus is one of high risk factors of ischemic brain injury, but the clinical interventions of ischemic brain damage in patients with diabetes are poorly reported. In our previous study, we demonstrated that inhibition of Rac1 played an important role not only in the treatment of ischemic brain damage in rats with diabetes mellitus, but also in the protection against cerebral ischemic injury by promoting mitophagy. In this progress, we confirmed the expression of LncRNA-MEG3 is up-regulated in the mitochondria and the inhibition of LncRNA-MEG3 could abrogate neuroprotection induced by Rac1 lentivirus. Our results also proved FUNDC1, a key factor involved in mitophagy, was the mitochondrial protein interacting with LncRNA-MEG3. Based on these findings, we assume Rac1-LncRNA-MEG3-FUNDC1 signaling pathway may mediate the mitophagy during cerebral ischemic injury, but the precise mechanism is not clearly defined. Therefore, this proposal is aimed to expound the exact function and molecular pathway of LncRNA-MEG3 in mitophagy regulation and the possible molecular mechanisms of the interaction between LncRNA-MEG3 and FUNDC1 in mitochondria by the methods of diabetic ischemic injury models both in vivo and in vitro, LncRNA mimic/inhibitor transfection, bioinformatics analysis and signaling transduction examination. Ultimately we intend to provide novel theoretical basis and strategy for diabetic cerebral ischemic injury.