血浆外泌体miRNA-200家族作为抗氧化应激调控因子早期诊断精索静脉曲张所致弱精子症可行性研究

Varicocele (VC) is the main cause of asthenospermia, but there are 30-50% of these patients still had asthenospermia after surgery. Oxidative stress is the leading factors leading to asthenospermia in VC patients, however, its mechanism is unknown. Several studies have shown that plasma exosomal miRNAs had a significant effect in the early diagnosis of the some diseases. Our previous study found that there was a significant increase of plasma exosomal miRNA-200 family in the patients with improved sperm motility after surgery compared with those without improvement of sperm quality. And we preliminarily proved that miR-200 family could effectively suppress MAPKs signal pathway. It is suggested that the miR-200 family of plasma exosomes might be a robust molecular marker to identify asthenospermia caused by VC in the early stage. Accordingly, in this project, we intend to investigate the anti-asthenospermia role of plasma exosomal miRNA-200 family in vivo and in vitro; In addition, we plan to elucidate the molecular mechanism of whether plasma exosomal miR-200 family play its role of antispermatogenic function via regulating MAPKs signal pathway; Finally, we intend to the optimal cut-off of miRNA-200 family for diagnosing asthenospermia caused by VC, and prospectively validated this optimal cut-off in a large prospective cohort of patients. The feasibility of miRNA-200 family as an anti-oxidative stress regulator in the early diagnosis of asthenospermia caused by varicocele was analyzed and validated in this study.

精索静脉曲张（Varicocele,VC）是弱精子症的主要病因，术后30-50%患者仍表现为弱精子症。氧化应激是VC致弱精子症的首要因素，其机制不明。最新研究表明血浆外泌体miRNAs具有抗氧化应激作用，且在疾病早期诊断中成效显著。我们前期研究发现miR-200家族在VC术后精子活力改善与不改善病例中表达差异显著，并初步证实miR-200家族可抑制MAPKs。提示血浆外泌体miR-200家族可能具有早期诊断VC所致弱精子症的潜在指标。据此，本项目拟进一步通过体内外实验证实血浆外泌体miR-200家族抗生精功能损害这一新功能；阐明血浆外泌体miR-200家族通过抑制MAPKs抗氧化应激保护生精功能的分子机制;并通过训练和验证多阶段构建并验证血浆外泌体miR-200家族诊断VC所致弱精子症的最佳阈值。进而阐明血浆外泌体miR-200家族作为抗氧化应激因子早期诊断VC所致弱精子症的可能性。

精索静脉曲张（Varicocele,VC）是弱精子症的主要病因，术后30-50%患者仍表现为弱精子症。氧化应激是VC致弱精子症的首要因素，其机制不明。本项目首先通过银夹新方法与传统左肾静脉半缩窄方法构建精索静脉曲张大鼠动物模型，发现银夹新方法可安全有效，方便快捷构建精索静脉曲张动物模型，为研究精索静脉曲张致睾丸生精损伤奠定了基础；后续通过构建GC1和TM4细胞氧化应激模型，体外实验发现miR-200a可靶向抑制MAPK信号通路减轻睾丸生精细胞氧化损伤，初步表明miRNA-200a可能通过抑制MAPK信号通路发挥抗氧化应激作用；并进一步通过临床样本分析发现精浆miRNA-200a可作为诊断精索静脉曲张是否合并弱精子症的一个潜在生物标志物。本项目采用银夹新方法构建了精索静脉曲张大鼠动物模型，为后续研究精索静脉曲张体内实验奠定了基础；并通过体外实验及临床样本验证初步揭示了精浆miRNA-200a通过抑制MAPK信号通路抗氧化应激这一生物学作用，可作为评估精索静脉曲张患者合并弱精子症的一个潜在生物标志物，有一定的转化价值。

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