miR-21通过VHL-Hif1-a及PTEN-AKT通路对颅脑创伤后神经-血管单元修复的作用及机制研究

The neurovascular unit (NVU) is a functional unit composed of groups of neurons, gliocytes, vascular endothelial cells, and extracellular matrix. The interactions of these components are capable of maintaining homeostasis in brain. Promoting the repairment of neurovascular unit after injury is crucial for the treatment of secondary brain injury and the management of TBI. The miRNA study in TBI has not been widely reported. In our previous study, we have confirmed that the expression level of miR-21 in the traumatic focus of rat brain increases apparently after TBI. Besides, up-regulation of miR-21 level in the brain can improve the neurological function after TBI. However, the function and mechanism of miR-21 in the repairment of NVU after injury has not been elucidated. Based on these findings, experiments on transgenic animal model and in vitro cell models are designed to study the function of miR-21 on cellular apoptosis, angiogenesis and blood-brain barrier repairment in the traumatic focus, thus clarify its impact on the NVU repairment after TBI. Besides, VHL-HIF1-α and PTEN-AKT signaling pathway are studied in order to explain the mechanism of how miR-21 exerts the above functions. The outcome of our proposed research will deepen the knowledge of the repairment mechanism of NVU after injury. It will also provide insights into developing a novel therapeutic approach of miR-21 gene therapy on TBI.

神经血管单元（NVU）是由神经元、神经胶质细胞、血管内皮细胞及细胞外基质等构成的功能单元，通过其中各种成分的相互作用维持脑组织内环境稳态。促进颅脑创伤（TBI）后NVU修复是治疗继发性脑损伤、救治TBI的关键。 miRNA在TBI领域中的研究报道较少。我们已发表的结果证实：TBI大鼠脑创伤灶miR-21表达量较伤前明显升高；上调脑组织miR-21表达量可以促进TBI后神经功能的恢复。但miR-21对NVU损伤后修复的影响及作用机制尚不清楚。 本研究拟通过转基因动物和体外细胞实验：1.明确miR-21对TBI后脑组织细胞凋亡、血管生成修复和血脑屏障修复的影响，进而探明其对NVU修复的作用；2.探讨miR-21产生上述作用的机制，研究VHL-HIF1-α及PTEN-AKT通路在该过程中的表达变化。本研究将加深对NVU损伤后修复机制的理解，为建立TBI后miR-21基因治疗的新方法提供理论依据。

神经血管单元（NVU）是由神经元、神经胶质细胞、血管内皮细胞及细胞外基质等构成的功能单元，通过其中各种成分的相互作用维持脑组织内环境稳态。促进颅脑创伤（TBI）后 NVU 修复是治疗继发性脑损伤、救治 TBI 的关键。miRNA 在 TBI 领域中的研究报道较少。我们已发表的结果证实：TBI 大鼠脑创伤灶 miR-21表达量较伤前明显升高；上调脑组织 miR-21 表达量可以促进 TBI 后神经功能的恢复。但miR-21 对 NVU 损伤后修复的影响及作用机制尚不清楚。本研究通过观察TBI后脑组织内miR-21的表达变化，明确了脑组织 miR-21 表达水平与 TBI 预后间的关系；明确了 miR-21 在 TBI 后 NVU 修复中的作用；探讨了 miR-21 影响 TBI 后 NVU 修复的作用机制；通过体内体外实验调控 miR-21 表达水平，检测了 PTEN-AKT 通路上凋亡及血管生成修复相关因子的表达情况，并评价了神经元凋亡情况。探讨了 miR-21 通过 PTEN-AKT 通路，影响 TBI 后细胞凋亡及血管生成修复的作用机制，结果发现：TBI后神经元和内皮细胞内升高的miR-21可以通过PTEN-AKT通路抑制细胞凋亡促进血管生成修复，为TBI后神经功能的恢复治疗提供了一个新的思路和方法。