NF-κB信号通路抑制剂Bay117082调节精子运动新机制及其应用的研究

Recent investigations indicate that male infertility is gradually increasing. The clinical manifestation of male sterility is azoospermia, oligospermia, teratozoospermia or asthenospermia. Among them, the asthenospermia is the most common. Therefore, it is imminent to strengthen the research of sperm health from the basic and application aspects. Under the support of the previous National Natural Science Foundation project, we found that nuclear factor κB inhibitor Bay117082 could significantly promote the movement of sperm in mice. The canonical nuclear factor-κB (NF-κB) signaling pathway mediates activation and subsequent entry of NF-κB proteins into nucleus and, thereby, regulates specific immunological processes including inflammatory diseases and cancers. However, there may be no complete NF-κB pathway in the sperm because sperm transcription and translation have come to a halt. Therefore, the NF-kB pathway and its inhibitor Bay117082 may exert a new mechanism of action on sperm motility. In a follow-up study, we have found that Bay117082-induced promotion of sperm motility is closely related to glucose utilization. Moreover, the preliminary results show that Bay117082 can significantly improve the motility of asthenospermia and frozen sperm. These results indicate that Bay117082 has a good prospect of clinical application. Based on our previous works, we will further investigate the molecular mechanism of Bay117082 in sperm motility and its potential clinical application. the important results will be achieved to clarify the molecular mechanism of Bay117082 in the regulation of sperm motility and identify the role of Bay117082 in improving the motility of weak sperm and frozen sperm. The expected achievements will be of helps not only in better understanding the molecular mechanisms of sperm motility, but also in providing some new ideas for male infertility.

近年调查表明，不育男性日益增加。临床主要表现为无精、少精、畸精、弱精等，其中弱精即精子运动缺陷尤为多发。所以，加强精子健康研究迫在眉睫。在以往面上项目资助下，我们发现了NF-κB信号通路抑制剂Bay117082能够显著促进小鼠精子运动。由于NF-κB通路是激活NF-κB蛋白进入细胞核调控转录使得细胞产生抗炎、抗肿瘤等效应。而精子核浓缩后转录和翻译均已停止，这样NF-κB途径及其抑制剂Bay117082可能在精子中具有新的调控机制。在后续研究中，我们新发现Bay117082促进精子运动与葡萄糖利用相关。而且，初步结果表明，Bay117082能够显著提高冷冻后精子和患者弱动精子的运动能力，显示了良好的应用前景。本项目拟结合小鼠模型进一步探索Bay117082调节精子运动的分子机制及其在临床上应用的潜能。以期揭示Bay117082调节精子运动的新机制，提供Bay117082在改善弱精、冷冻精子的运动及质量方面的临床潜在应用依据，获得原始创新性结果和数据。成果不仅有助于阐明精子运动调控的分子机制，亦为解决男性不育提供新的启发。

近年研究表明，男性精液质量和生育力仍在逐年下降。临床患者以弱精即精子运动不足或缺陷尤为多发。所以，改善精子活力提高生育力迫在眉睫。以往工作中，通过对小分子化合物筛选，我们发现了NF-κB通路抑制剂Bay117082能够显著促进小鼠精子运动。NF-κB通路是激活NF-κB蛋白组分进入细胞核调控转录使得细胞产生抗炎、抗肿瘤等免疫效应。而精子形成后，细胞核高度浓缩，转录和翻译均已停止，这样NF-κB途径及其抑制剂Bay117082可能在精子中具有新的调控机制。因此，本项目拟进一步探索NF-κB通路在精子中的表达分布特征及其抑制剂Bay117082调节精子运动的分子机制和在临床上的应用潜能。.首先我们检测了人精子中NF-κB通路的蛋白组分，发现IKKA、IKKB、IKKγ、p105/50、p100/52、RELA/B、c-REL、IKBA等大部分蛋白都在精子中表达，并主要分布于精子中段的线粒体部位。其中IKKA/B、RELA、IKBA等蛋白磷酸化呈现组成型存在，且可被获能液BWW进一步增强。NF-κB途径中关键蛋白IKBA磷酸化抑制剂Bay117082能够显著促进人精子的运动，相反，IKBA磷酸化激活剂LPS可以抑制精子的运动，但是，Bay117082不能对IKBA敲除的精子发挥作用，提示Bay117082是特异性抑制IKBA蛋白磷酸化来调控精子的运动。在作用机制上，利用非靶向代谢组学和药理学方法表明，Bay117082主要是通过下调乙酰辅酶A羧化酶表达，进而增强了脂肪酸的β氧化提高能量ATP水平促进人精子运动。.本研究成果不仅为人精子运动调控机理的阐明提供了新的资料和启发，亦为临床弱精子运动的改善提供新的候选分子。同时丰富了NF-κB信号通路的非经典途径即非转录调节的知识，加深了对NF-κB新功能、新机制的理解。.截止结题时，已发表标注此项目批准号的SCI研究论文4篇，其中3篇影响因子（JCI分区Q1）大于5.0；投稿评审中SCI研究论文1篇（JCI分区Q1，IF>5.0）；参与编写论著《发育源性疾病》1本；培养研究生毕业并获得博士学位1名、硕士学位1名，出站博士后1名。参与并作会议邀请报告5场。.