miR-325调控Lhx3影响新生儿缺氧缺血脑病后生物节律的机制研究

Hypoxic-ischemic encephalopathy (HIE), a severe syndrome occurred during laboring, lacks specific diagnosis markers and effective treatments. Among patients of HIE, many develop circadian rhythm dysfunctions, although the underlying mechanisms are largely unknown. Recent studies revealed close relationships between microRNAs and circadian rhythm regulation. By a high throughput microRNA screening, we targeted one microRNA, miR-325, which was robustly expressed in a high level in the pineal gland after HIBD. In our previous studies, we showed that over-expression of miR-325 hampers AANAT expression in the pineal gland, and therefore the rhythmic synthesis of MT after HIBD. In this study, we first established miR-325 KO mice using CRISP/Cas 9 technique and analyzed its phenotypes. Meanwhile, we will also establish tissue specific (pineal gland) over-expression and KO of miR-325 mice to study how miR-325 is involved in circadian rhythm regulation. In addition, we will focus on a new target of miR-325--Lhx3 to see how miR-325 regulates Lhx3 to effect circadian rhythm. Taken together, we will utilize techniques including primary cell culture, animal and surgery models, clinical studies to reveal the function and mechanisms of miR-325 in regulating homeostasis and circadian during development and pathological conditions. Our study will therefore provide new insights on the pathophysiological mechanisms of circadian dysfunction and potential therapeutic target after HIE.

新生儿缺氧缺血性脑病（HIE）是常见的围产窒息后严重的并发症，至今仍缺乏特异性诊疗手段。其中表现出生物节律紊乱的患儿预后不良，机制不明。随着miRNA与生物节律的密切关系逐渐被认识，我们通过基因芯片，筛选出差异表达的miR-325作为候选基因，并发现其能通过影响松果体功能，参与HIE后生物节律紊乱的发生。在我们成功获得miR-325基因敲除小鼠并发现显著表型过程中，我们锁定了新靶点——Lhx3。本项目拟应用组织特异性敲除及过表达小鼠对miR-325的节律相关表型展开研究；同时从原代培养松果体细胞、模式动物、手术模型动物、临床病人等不同层面，深入研究miR-325参与缺氧缺血后节律紊乱的机制，并阐明miR-325是否亦通过调控Lhx3影响HIE后生物节律。将为HIE及其远期后遗症的防治提供新靶标。

新生儿缺氧缺血性脑病（HIE）是常见的围产窒息后严重的并发症，至今仍缺乏特异性诊疗手段。其中表现出生物节律紊乱的患儿预后不良，机制不明。随着miRNA与生物节律的密切关系逐渐被认识，我们通过基因芯片，筛选出差异表达的miR-325作为候选基因，并发现其能通过影响松果体功能，参与HIE后生物节律紊乱的发生。在我们成功获得miR-325基因敲除小鼠并发现显著表型过程中，我们锁定了新靶点——Lhx3。本项目应用组织特异性敲除及过表达小鼠对miR-325的节律相关表型展开研究；同时从原代培养松果体细胞、模式动物、手术模型动物、临床病人等不同层面，深入研究miR-325参与缺氧缺血后节律紊乱的机制，并阐明miR-325是否亦通过调控Lhx3影响HIE后生物节律。将为HIE及其远期后遗症的防治提供新靶标。