The role of pineal microRNA-325 in regulating circadian rhythms after neonatal hypoxic-ischemic brain damage  

作　　者：Ning Sha Hua-Wei Wang Bin Sun Min Gong Po Miao Xiao-Lu Jiang Xiao-Feng Yang Mei Li Li-Xiao Xu Chen-Xi Feng Yuan-Yuan Yang Jie Zhang Wen-Jing Zhu Yuan-Yuan Gao Xing Feng Xin Ding 

机构地区：[1]Soochow Key Laboratory of Prevention and Treatment of Child Brain injury,Children’s Hospital of Soochow University,Suzhou,Jiangsu Province,China [2]Department of Pediatrics,Affiliated Huai’an Hospital of Xuzhou Medical University,Huai’an,Jiangsu Province,China [3]Pediatrics Research Institute,Children’s Hospital of Soochow University,Suzhou,Jiangsu Province,China [4]Department of Pediatrics,The First Affiliated Hospital of Soochow University(Dushuhu Branch),Suzhou,Jiangsu Province,China [5]Cambridge-SU Genomic Resource Center,Soochow University,Suzhou,Jiangsu Province,China [6]Clinical Laboratory,Children’s Hospital of Soochow University,Suzhou,Jiangsu Province,China

出　　处：《Neural Regeneration Research》2021年第10期2071-2077,共7页中国神经再生研究（英文版）

基　　金：This study was supported by the National Natural Science Foundation of China,Nos.81871193(to XD),81671532(to BS),81771625&81701490(to XF),81801505(to MG);Jiangsu Provincial Medical Youth Talent of China,Nos.QNRC2016763(to XD),QNRC2016758(to LXX),QNRC2016762(to ML);the Science and Technology Project of Suzhou City of China,No.SS201709(to XD);the Natural Science Foundation of Jiangsu Province of China,No.BK20180205(to XD);the Training Program Foundation for Health Talents of Gusu of China,No.GSWS2019049(to XD);the Jiangsu Provincial Key Medical Discipline of China,No.ZDXKA2016013(to XF);the Jiangsu Province Women and Children Health Research Project of China,No.F201750(to LXX);the Pediatric Clinical Center of Suzhou City of China,No.Szzx201504(to XF);Suzhou Industrial Technology Innovation Project of China,No.SYS201765(to LZ);the Project of Suzhou Science,Education and Health and Technology,China,No.KJXW2018018(to ML).

摘　　要：Circadian rhythm disorder is a common,but often neglected,consequence of neonatal hypoxic-ischemic brain damage(HIBD).However,the underlying molecular mechanisms remain largely unknown.We previously showed that,in a rat model of HIBD,up-regulation of microRNA-325(miR-325)in the pineal gland is responsible for the suppression of Aanat,a key enzyme involved in melatonin synthesis and circadian rhythm regulation.To better understand the mechanism by which miR-325 affects circadian rhythms in neonates with HIBD,we compared clinical samples from neonates with HIBD and samples from healthy neonates recruited from the First Affiliated Hospital of Soochow University(Dushuhu Branch)in 2019.We found that circulating miR-325 levels correlated positively with the severity of sleep and circadian rhythm disorders in neonates with HIBD.Furthermore,a luciferase reporter gene assay revealed that LIM homeobox 3(LHX3)is a novel downstream target of miR-325.In addition,in miR-325 knock-down mice,the transcription factor LHX3 exhibited an miR-325-dependent circadian pattern of expression in the pineal gland.We established a neonatal mouse model of HIBD by performing doublelayer ligation of the left common carotid artery and exposing the pups to a low-oxygen environment for 2 hours.Lhx3 mRNA expression was significantly down-regulated in these mice and partially rescued in miR-325 knockout mice subjected to the same conditions.Finally,we showed that improvement in circadian rhythm-related behaviors in animals with HIBD was dependent on both miR-325 and LHX3.Taken together,our findings suggest that the miR-325-LHX3 axis is responsible for regulating circadian rhythms and provide novel insights into the identification of potential therapeutic targets for circadian rhythm disorders in patients with neonatal HIBD.The clinical trial was approved by Institutional Review Board of Children’s Hospital of Soochow University(approval No.2015028)on July 20,2015.Animal experiments were approved by Animal Care and Use Committee,School of Medicine

关 键 词：brain injury circadian rhythm hypoxic-ischemic brain damage miRNA NEONATE pineal gland SLEEP transcription factor 

分 类 号：R722.1[医药卫生—儿科]