Lnc-MALAT1调控糖尿病血管病内皮前体细胞的归巢及生物学功能机制研究

Diabetes angiopathies (DA), the main cause to death of diabetic patients, has become an important research direction, although the detailed mechanism of pathogenesis is unclear. It is known that Endothelial progenitor cells (EPCs) which derived from myeloid can homing to the damaged area to repair the damaged blood vessels, in which MAPK/JNK signaling pathway play an important role in adjustment of homing and biological function to EPCs, when blood vessel was damaged or tissue was ischemic. Our preliminary results showed that the normal biological function of EPCs were affected by the increased expression of long chain non-coding RNA (LncRNA)-MALAT1 in patients. Furthermore, our results also demonstrate that MiR-22-3p is abnormally expressed in the DA patients and regulates the biological function of EPCs via MAPK/JNK signaling pathway. Bioinformatic analysis and molecular and cellular experiments indicate that MiR-22-3p was regulated by Lnc-MALAT1, suggesting that Lnc-MALAT1 can regulation MAPK/JNK signaling pathway indirectly through targeting MiR-22-3p and influence the biological function of EPCs cells and promote angiopoiesis of EPCs and accelerate wound repair process. Therefore, here we proposed to explore the mechanism of EPCs homing by using molecular, cellular and animal experiments tools. We believe our results will shed a light on prevention and control of diabetic angiopathies including new thoery.

糖尿病血管病(diabetic angiopathies，DA)是糖尿病致死致残的主要原因，发病机制尚不清楚。研究证实血管损伤发生后，内皮前体细胞(endothelial progenitor cells，EPCs)可特异性的归巢到受损部位，修复损伤血管。本课题组前期研究发现DA患者Lnc-MALAT1表达上调，抑制EPCs生物学功能；同时还发现EPCs的MiR-22-3p也存在异常表达，其可能通过影响MAPK/JNK信号通路，影响EPCs生物学功能。进一步生物信息学等实验证实MiR-22-3p是Lnc-MALAT1下游调控靶点。因此我们推测Lnc-MALAT1可能通过靶向调控MiR-22-3p 干扰MAPK/JNK通路，而影响EPCs生物学功能。因此，本项目拟从临床、动物实验等层面探讨Lnc-MALAT1影响EPCs生物学功能机制，为DA的防治提供新的治疗靶点和理论基础。

本项目本研究探讨糖尿病机体中 EPCs 归巢等生物学功能的改变和调控机制，通过对60例糖尿病患者EPCs的评价，在高糖诱导的EPCs衰老后，评价来自脂肪干细胞（SDSCs）外泌体的治疗作用。此外，还研究了体外以及糖尿病鼠模型中，ADSCs外泌体和Nrf2过表达的作用。发现高糖环境中ADSCs分泌的外泌体促进了EPCs的增殖和血管行成，而过表达Nrf2增强了这种保护作用。用ADSCs外泌体过表达Nrf2处理糖尿病鼠足部溃疡，明显降低了溃疡区域。在损伤去发现：增加肉芽组织行成、血管再生及生长因子表达量，同时降低了炎症和氧化应激蛋白水平。数据表明ADSCs外泌体能潜在的促进伤口愈合，特别是当Nrf2过表达，因此外泌体移植可能适用于糖尿病血管病的临床治疗。为防治和早期诊断糖尿病提供新的理论基础和治疗靶点。本项目完成发表SCI论文2篇，培养博士3名，硕士研究生3名。