miR-325-3p介导缺氧缺血性脑损伤后松果体功能紊乱的机制研究

项目名称： miR-325-3p介导缺氧缺血性脑损伤后松果体功能紊乱的机制研究

项目编号： No.81501291

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 丁欣

作者单位： 苏州大学

项目金额： 18万元

中文摘要： 新生儿缺氧缺血性脑损伤(HIBD)常遗留昼夜节律紊乱，但机制未明。临床研究显示松果体功能损伤导致的神经内分泌障碍可能是主要病理过程。本课题工作基础提示HIBD后大鼠松果体和血清中褪黑素（MT）合成关键酶AANAT，MT 节律长期表达紊乱，而miR-325-3p 表达持续升高。生物信息学预测Aanat是miR-325-3p下游靶标, 因此我们设想：HIBD后miR-325-3p的异常升高通过影响Aanat的表达导致松果体分泌MT节律紊乱。本课题拟在细胞层面验证miR-325-3p和Aanat的相互作用，并在组织病理和行为学层面探索miR-325-3p对松果体功能的远期影响。同时模拟HIBD病理，研究不同伤害刺激对miR-325-3p、Aanat表达影响。miR-325-3p与松果体功能的关系未见报道，因此，本研究为HIBD后节律紊乱的机制研究和防治提供了新靶标。

中文关键词： 微小RNA；新生儿缺氧缺血性脑病；松果体；生物节律；AANAT

英文摘要： Hypoxic-ischemic brain damage (HIBD) survivals are commonly accompanied by circadian rhythm disorders, although the underlying mechanisms are largely unknown. Clinical studies indicated that the neuroendocrine disorders induced by pineal injury might be a key pathophysiologic factor. Our previous research suggested a chronic impairment of Aanat, a key regulator for melatonin (MT) synthesis, MT expression in the pineal gland and serum of rats with HIBD. Meanwhile, we identified that one microRNA, miR-325-3p, was robustly expressed in a high level in the pineal gland after HIBD. Given that Aanat mRNA is bioinfomatically predicted as a downstream target of miR-325-3p, we hypothesized that the over-expression of miR-325-3p hampers AANAT expression in the pineal gland, and therefore the rhythmic synthesis of MT after HIBD. To test our hypothesis, we intend to analyze whether miR-325-3p interacts with Aanat mRNA and how miR-325-3p affects its expression. We will also explore the long-term effects on pathology and behavioral changes induced by miR-325-3p overexpression or silencing in vivo. Last, we will investigate how different stimuli that mimic HIBD affect the expression of miR-325-3p, AANAT in cultured pineal gland cells. The role of miR-325-3p on pineal function has not been reported, our study therefore provides new insights on the pathophysiological mechanisms of circadian dysfunction and potential therapeutic target after HIBD.

英文关键词： microRNA;HIE;pineal gland;circadian rhythm;AANAT