受超级增强子调控的circRNA-2341通过miR-325-3p/Bhlhe41介导缺氧缺血松果体损伤致节律紊乱的机制研究

新生儿缺氧缺血性脑损伤(HIBD)常遗留昼夜节律紊乱，非编码RNA与节律紊乱发生密切相关，但调控机制未明。我们预实验发现：HIBD后大鼠松果体circRNA-2341表达上调，过表达circRNA-2341能造成松果体损伤并减少褪黑素分泌；HIBD后miR-325-3p表达减弱并结合到circRNA-2341，上调miR-325-3p能增加褪黑素分泌；报告基因证实miR-325-3p调控靶基因Bhlhe41且HIBD后Bhlhe4表达上调；circRNA-2341基因上游存在超级增强子（SE），HIBD和氧剥夺/复氧模型中SE活性增强。因此，本项目拟以HIBD大鼠为模型，circRNA-2341作为切入点，从整体、细胞和分子水平阐明受SE调控的circRNA-2341通过miR-325-3p/Bhlhe41对松果体损伤后昼夜节律紊乱的调节机制，以期为HIBD治疗提供新思路。

Neonatal hypoxic-ischemic brain damage (HIBD) often leaves circadian rhythm disturbances. Non-coding RNA is closely related to the occurrence of rhythm disturbances, but the regulatory mechanism is unknown. Our pre-experiments found that the expression of circRNA-2341 in the pineal gland of rats was up-regulated after HIBD, and overexpression of circRNA-2341 could cause pineal gland damage and reduce melatonin secretion; miR-325-3p can bound to circRNA-2341 and was reduced after HIBD, up-regulation of miR-325-3p can increase melatonin secretion; reporter gene confirmed that miR-325-3p regulates the target gene Bhlhe41 and Bhlhe4 expression is up-regulated after HIBD; Super enhancer (SE) exists in the upstream of circRNA-2341, and SE activity is enhanced in HIBD and oxygen deprivation /reoxygenation models.Therefore, this project intends to use HIBD rats as a model and circRNA-2341 as the breakthrough point on the whole, cellular and molecular level to clarify the mechanism of circRNA-2341 modulated by super enhancer regulates rhythm disorders of hypoxic ischemia via targeting miR-325-3p/Bhlhe41. Our research aims to provide new ideas for the treatment of HIBD.