circZfp609/miR-185-5p介导氯胺酮致发育期神经毒性的分子机制

Children may receive invasive diagnostic or surgical procedures that require general anesthesia as a part of their medical care. However, retrospective cohort studies suggest that repeated or lengthy use of general anesthetics during surgeries or procedures in children younger than 3 years may affect the development of children’s brains and trigger long-term cognitive dysfunction of children, and the underlying mechanism remains unclear. Recent studies have shown that non-coding RNAs play a vital role in many human diseases. Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs that form a covalently closed continuous loop. The stability and specific expression of circRNAs make them very interesting candidates as biomarkers for diseases. In this study, we found that knockdown of circRNA Zfp609 (circZfp609) could alleviate neuronal apoptosis induced by ketamine. Furthermore, circZfp609 could regulate the ketamine induced neurotoxicity via miR-185-5p. So we raise a novel hypothesis: “The neurotoxicity induced by ketamine in developing mice is mediated by circZfp609/miR-185-5p”. To confirm this hypothesis and explain how circZfp609 regulates miR-185-5p expression, we use the neurotoxicity model induced by ketamine in neonatal mice. This study will help to further understand the biologic function of circZfp609 in the ketamine-induced neurotoxicity in developing mice, which provides a new perspective for the control of the ketamine induced neurotoxicity.

全身麻醉广泛应用于婴幼儿的外科手术、介入治疗等诊疗过程，回顾性研究发现小于3岁的婴幼儿重复或长时间使用全麻药可显著提高其青春期出现认知功能损害的概率，但具体调节机制尚不明确。研究发现，非编码RNA可参与多种生理病理过程，其已逐渐成为临床诊断的生物标志物或潜在的防治靶标。我们前期研究发现降低环状非编码RNA Zfp609（circZfp609）可显著减轻儿科常用全麻药氯胺酮引起的神经凋亡，而miR-185-5p可能在此过程中发挥重要作用。基于此，我们提出“circZfp609/miR-185-5p介导了氯胺酮诱导的发育期神经毒性”这一科学假说。本项目拟利用氯胺酮致发育期神经毒性的体内外模型，阐明circZfp609的生物学功能及分子机制，并探索可调控氯胺酮致发育期神经毒性的circZfp609/miR-185-5p的下游靶基因，以期为探究氯胺酮致发育期神经毒性的防治靶标提供理论基础。

3岁以下婴幼儿重复或长时间使用全麻药可显著提高其青春期出现认知功能损害的概率，但具体调节机制尚不明确。近期研究表明，非编码RNA可参与多种生理病理过程，其已逐渐成为临床诊断的生物标志物或潜在的防治靶标。本研究中，我们取得一系列重要的研究进展，发现降低环状非编码RNA 659（circ659）可显著减轻儿科常用全麻药氯胺酮引起的神经发育毒性，并且其可直接作用于miR-483-5p。通过本项目的基础研究，为后续探究氯胺酮致发育期神经毒性的防治靶标提供了理论基础。在本项目执行期间，共发表学术论文4篇（2篇SCI，2篇中文核心期刊），授权发明专利1项，培养硕士研究生1名。