芳香化酶调控大鼠缺血性脑卒中后星型胶质细胞可塑性的性别差异性及其机制研究

There are notable sex differences in prognosis of stroke. Stroke has no gender-specific treatment strategies at present since the under molecular of these sex differences remains is still unclear. These gender differences are still a blind spot which is often overlooked. It is known that aromatase, 18 kDa translocator protein (TSPO) and the plasticity of astroglia exert important role in neural repair post-stroke. Our preliminary experiment indicated that the expressions of aromatase and TSPO was significantly higher in peri-infarct zones after focal cerebral ischemia (MCAO). We observed significant positive linear correlation between aromatase and TSPO in the peri-infarct zone in female rats, which was opposite in male. The expression of TSPO was higher, the nerve functional recovered better. These results suggested that aromatase may influence the prognosis of stoke via interfering with TSPO expression, and this process was sex-specific. Further studies will be carried out to investigate the change of the expression of TSPO and the plasticity of astroglia by downregulating the aromatase expression and interfering PKA signal pathway in different gender rat post-MCAO, thus elucidating the intrinsic relationship between aromatase, TSPO and astrocyte plasticity and the difference of this correlation across sex. The goal is to unveil the molecular basis of sex differences in ischemic stroke, and provide the vital basis to design sex-specific therapies.

脑卒中预后存在明显性别差异，由于其背后分子机制尚未明确，目前针对脑卒中患者仍缺乏性别特异性治疗。这种性别差异仍是目前常被忽视的一个盲点。已知芳香化酶、线粒体18kDa转运蛋白（TSPO）及星型胶质细胞可塑性在脑卒中后神经修复中均发挥重要作用。我们在前期实验中发现雌性大鼠脑缺血(MCAO)后，梗死周围组织芳香化酶及TSPO的表达均显著增加且二者之间呈明显线性正相关；而在雄性大鼠中却呈线性负相关；且TSPO表达水平越高，神经功能恢复越好，提示芳香化酶可能通过干预TSPO表达影响脑卒中预后，且该过程具有性别差异性。本项目拟在不同性别MCAO大鼠中，下调芳香化酶及干预PKA信号传导后，观察星型胶质细胞TSPO表达及其可塑性程度变化，阐明芳香化酶、TSPO及星型胶质细胞可塑性之间的内在联系以及在性别中差异,有助于揭示缺血性脑卒中性别差异的分子基础，有望为未来开发性别特异性的脑卒中治疗奠定重要基础。

脑卒中预后无论是在临床研究还是动物实验研究中都表现出明显性别差异。星型细胞可塑性对于缺血性脑卒中预后有着重要作用。本团队一直致力于雌激素在中枢神经系统损伤修复中作用的研究。芳香化酶是雌激素合成关键酶，决定脑组织局部雌激素水平。本课题通过制作不同性别的MCAO大鼠模型，测定不同性别大鼠脑梗死周围芳香化酶水平，结果发现雌性大鼠MCAO术后，脑梗死周围组织中芳香化酶水平明显高于雄性MCAO大鼠。我们进一步通过芳香化酶抑制剂来曲唑干预MCAO大鼠，结果显示芳香化酶受抑制后，大鼠脑梗死体积较对照组大鼠明显增加，两种性别大鼠TSPO及GFAP表达均明显下调，且TSPO、GFAP及芳香化酶三者之间呈现明显正相关。推测芳香化酶可能通过TSPO影响星型细胞可塑性进而影响脑卒中预后，不同性别大鼠脑梗死周围芳香化酶表达的差异可能是导致脑卒中预后不同的重要原因。本项目可以丰富人们对于脑卒中预后性别差异的认识。同时对于认识雌激素与星型胶质细胞可塑性之间关系提供了重要的启示性线索。本项目证实了雌激素在脑梗死中的神经保护作用。目前已有大型国际多中心临床研究尝试给予脑卒中患者雌激素替代治疗改善预后，但由于其存在的诸多副反应，在临床上应用受到广泛质疑。如能寻找一种可内源性增加脑内雌激素水平的方法，将弥补这一缺陷。因此，我们在本项目的基础上进一步探索了内源性增加雌激素水平的策略。我们开展了前瞻性临床研究，发现高频rTMS治疗脑损伤患者后，患者血清水平明显升高，且升高水平与患者预后密切相关。该研究结果为脑卒中患者康复治疗提供了新的雌激素治疗研究方向，从而改善脑损伤患者预后。本项目资助发表SCI论文5篇，协助培养硕士研究生2名。