褪黑素修复脓毒症新生儿脑室周边白质损伤的机制研究

A1星形胶质细胞介导的神经炎症导致脑室周边白质损伤(PWMD) 是脓毒症新生儿远期神经功能障碍发生的重要原因。我们发现：褪黑素(MT)可以促使脓毒症幼鼠PWM内星形胶质细胞A1向A2转化，修复PWMD，改善学习记忆能力。那么，MT促A1星形胶质细胞表型转化的机制是什么呢？有报道端粒酶高表达可以促星形胶质细胞向A2转化，JAK2是端粒酶上游关键调控分子。进一步实验显示：MT激活A1星形胶质细胞内JAK2，抑制MT受体1可下调其表达。由此，我们提出MT修复脓毒症PWMD新机制：通过MT1/JAK2-端粒酶促A1星形胶质细胞向A2转化。本项目拟进一步采用条件基因敲除小鼠、RNA干扰、微流控qPCR、电镜、原位杂交等方法，旨在获得MT促A1星形胶质细胞表型转化的可靠证据及调控其转化的关键“开关点”，阐明MT修复脓毒症PWMD的新机制，为确立MT治疗脓毒症新生儿远期神经功能障碍提供更充分的科学依据。

Neuroinflammatory response induced by A1 astrocyte play an important role in the pathogenesis of the periventricular white matter (PWM) damage (PWMD) in septic neonate, which would lead to neurological disorders in later life. We found that melatonin (MT) may promote the transformation of phenotype A1 astrocyte into A2, repair the PWMD of septic neonatal mice and improve learning and memory in later life. So, what is the mechanism of MT promoting the phenotype transformation of A1 astrocytes? Some studies have reported that overexpression of telomerase in the astrocyte could promote the phenotype transformation of A1 astrocyte into A2 and JAK2 is a key regulatory molecule in the upstream of telomerase. Preliminary data showed that MT may activate the JAK2 in the astrocyte and downregulate the expression of JAK2 through the inhibition of MT1. Therefore, we hypothesize that MT could induce the phenotype transformation of A1 astrocyte into A2 through the activation of MT1/JAK2-telomerase pathway in the PWM of septic neonatal mice, which was a new mechanism that MT may repair PWMD. Our study would obtain the reliable evidences of MT promoting the phenotype transformation of A1 astrocytes using conditioned knockout mice, siRNA, microfluidic qPCR, electronic microscopy, in situ hybridization etc. This study attempts to reveal the key "switching points" that MT promote the phenotype transformation of A1 astroctye and elucidate the new molecular mechanisms by which MT might repair the PWMD of septic mice. Our study would provide a more sufficient scientific basis for the establishment of MT in the treatment of the long-term neurological dysfunction of the newborn with sepsis.