BDNF相关microRNA的表达水平、基因型和精神分裂症病理症状、认知功能关系研究

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a crucial role in neurodevelopment and neuroplasticity. MicroRNAs (miRNAs) are small non-coding RNAs of about 22-nucleotides in length that regulate gene expression at post-transcriptional level. Involved in neural development and function, both BDNF and miRNAs have been consistently implicated in pathophysiology of schizophrenia and its associated cognitive deficits. The regulatory networks between BDNF and miRNAs have also been observed. However, to date, there has not been a study focusing on a set of BDNF-related miRNAs in relation to psychopathology and cognitive dysfunction in schizophrenia. In this project, we will compare the expression levels of 9 BDNF-related miRNAs (miR-137, miR-132/miR-212，miR-134, miR-16/miR-195，miR-206，miR-30a-5p/miR-30e) in peripheral blood mononuclear cells by real time PCR between first-episode schizophrenia patients and healthy controls. These 9 miRNAs have been reported by at least 2 independent studies reporting its association with schizophrenia or cognitive function and interaction with BDNF. In parallel with miRNA expression, serum BDNF levels and 4 single nucleotide polymorphisms (SNPs) including BDNF Val66Met (rs6265) and 3 SNPs of miRNAs will also be examined. For the clinical data collection, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) will be used for cognitive performance in all subjects and Positive and Negative Syndrome Scale (PANSS) for the psychopathology of patients. The genotype and expression levels of BDNF and miRNAs will then be analysed in relation to syndrome and cognitive dysfunction in schizophrenia and the interplay between BDNF genotype/expression and miRNA genotype/expression will also be examined. This project will provide a comprehensive understanding of the pathogenesis of cognitive deficits in schizophrenia, which may have important clinical prospects for clinical biomarkers and novel treatments.

脑源性神经营养因子(BDNF)和微小RNA(microRNA)在神经发育中起着重要作用，BDNF与miRNA之间还存在复杂相互作用，两者与精神分裂症病因及认知损伤紧密相关。目前我国尚缺乏BDNF相关miRNA的表达水平和基因型与精神分裂症发病机理、病症及认知损伤关系的系统研究。本课题将以中国汉族首次发作的精神分裂症患者和正常人为研究对象，通过ELISA、RT-PCR、SNP分析等分子生物技术，对比分析首发患者和对照人群中BDNF和BDNF相关miRNA的基因型、外周血单核细胞中BDNF和BDNF相关miRNA（miR-137, miR-132/miR-212，miR-134, miR-16/miR-195，miR-206，miR-30a-5p/miR-30e）表达水平，进而分析以上各因素及其交互作用与精神病理症状及认知功能的关联，为精神分裂症的临床诊断和新型药物治疗提供理论依据。

脑源性神经营养因子(BDNF)和微小RNA(microRNA)在神经发育中起着重要作用，BDNF与miRNA之间还存在复杂相互作用，两者与精神分裂症病因及认知损伤紧密相关。目前我国尚缺乏BDNF相关miRNA的表达水平和基因型与精神分裂症发病机理、病症及认知损伤关系的系统研究。本课题入组了首发精神分裂症患者307例，健康对照患者368例，评估了PANSS、RBANS和立体视觉，通过ELISA和TaqMAN技术检测BDNF SNPs分型和蛋白水平，也检测了DBH和PLA2G12A分型及ALB、TBIL和IL-18蛋白水平。此外，还入组了重性抑郁症患者，检测了IL-6、TG和ApoB蛋白水平。BDNF单倍型、DBH和PLA2G12A分型、BDNF、ALB、TBIL和IL-18蛋白水平在首发精神分裂症和健康对照组间存在显著差异。BDNF、DBH、PLA2G12A分型变化、BDNF、ALB、TBIL和IL-18蛋白水平变化与首发患者的临床表型具有显著相关性。相比健康对照组，首发患者组存在着严重的认知损伤和立体视觉损伤。重性抑郁症患者组IL-6和TG水平显著高于健康对照组，IL-6水平与患者持续注意分值呈正相关，TG水平与患者时间广度空间分值、延迟记忆分值和RBANS总分呈负相关，ApoB水平与患者即刻记忆呈负相关。相对于健康对照组，重性抑郁症患者RBANS总分、语言和延迟记忆分值显著减低。这些结果建议：BDNF、DBH和PLA2G12A基因是首发精神分裂症的易感基因,并影响患者临床表型；BDNF、ALB、TBIL和IL-18水平也涉及首发精神分裂症发病和临床表型。IL-6、TG和ApoB水平涉及重性抑郁症的发病和临床表型。.上述成果总结并发表国外学术SCI论文共9篇，总影响因子达31.057分，在国内刊物上发表8篇。课题成果将为精神分裂症的临床诊断提供了理论依据。