不孕不育症是一种生殖系统疾病，世界卫生组织将其定义为育龄夫妇在有12个月的定期无保护性交后未能正常妊娠(1)。据统计，全世界有多达1.86亿人患有不孕症。不幸的是，世界上不孕率最高的地区往往是那些难以获得辅助生殖技术的地区(2)。根据中国人口协会和国家计生委在2019年联名发布的《中国不孕不育现状调查报告》显示，中国的不孕不育率从20年前的2.5%-3%攀升到12.5%-15%左右，患者人数超过4000万，且呈现年轻化趋势。世界卫生组织已经将不孕不育症视为一个全球性健康问题，因为无法生育对发达国家和发展中国家的社会关系甚至医学都有深远的影响。
据统计，约30%-50%的不孕不育患者是由男性因素引起的，即男性不育症(3)。造成男性生殖障碍的因素很多(4-6)，目前主要有遗传因素、内分泌因素、免疫因素、生殖道感染、性功能障碍、输精管阻塞、睾丸生精功能障碍等。其中遗传因素约占男性不育的15%以上，日益成为研究男性生殖障碍机制的热点方向。
人内源性逆转录病毒 (HERV) 是在灵长类进化过程中，通过多种感染及整合已灭绝的外源性逆转录病毒而获得的，约占人类DNA的8%(7, 8)。根据引物结合位点识别的tRNA类型，HERV可分为至少31个家族，包括HERV-W(9), HERV-T(10), HERV-K(11), HERV-F(12), HERV-E(13)等。HERV的异常表达通常被认为与多种恶性肿瘤和疾病的发生发展相关，例如结肠癌(14)、乳腺癌(15)、多发性硬化(16)和神经退行性疾病(17)等。HERV家族中的大多数基因被沉默，但有些基因仍保持其功能。其中，HERV-W家族env蛋白 (人源性基因为syncytin-1，鼠源性基因为syncytin-a或syna)是其中一种拥有完整功能的蛋白。Syncytin-1是一种高度融合的膜糖蛋白，在负责受体识别和膜融合过程中发挥重要作用(18-20)。其异常表达与膀胱癌(21)、非小细胞肺癌(22)、先兆子痫(23)等显著相关。研究发现，与正常精子样本相比，弱精子症、少精子症和弱少精子症样本中syncytin-1及其受体SLC1A5的表达显著降低(24)，提示syncytin-1和SLC1A5表达降低可能是导致不育的原因之一。
纯合syncytin-a基因缺失小鼠在妊娠的11.5-13.5天之间死于子宫内，具有胚胎致死性(25)，因此，我们前期构建了前列腺组织特异性syncytin-a基因敲除小鼠模型。结合其他研究报道，发现以下几种信号通路与睾丸相关的雄性不育有关：PI3K/Akt/mTOR主要参与精子发生过程中下丘脑-垂体-性腺轴的调节、精原细胞和体细胞的增殖和分化(26)；JAK/STAT3信号通路破坏可以诱导睾丸间质细胞损伤(27)；破坏Keap/Nrfz信号通路导致大鼠的睾丸生精小管损伤，血管充血，精子密度降低(28)；TGF-β/Smad信号通路破坏可以使成年小鼠睾丸体积变小，精子产量降低，生育力受损(29)；Wnt/β-catenin信号通路能够调控人精原干细胞增殖和凋亡(30)。但目前尚没有报道详细阐述syncytin-a基因缺失在雄性不育中的信号通路。结合我们的预实验结果，我们做出了以下假说（图1）：前列腺组织特异性syncytin-a基因敲除后,可能通过激素作用于睾丸，导致睾丸内的信号通路异常改变，最终造成精子畸形及雄性生殖障碍。我们在预实验中还发现：前列腺组织特异性syncytin-a基因缺失会导致雄性小鼠发育迟缓，精子的数量减少和形态畸形。
图1 Syncytin-a条件性基因敲除导致雄性不育的假说图
本项目旨在进一步研究syncytin-a基因缺失后雄性小鼠性生殖器官的形态变化、精子异常、及引起异常的分子机制和信号通路，来明确syncytin-1是否可能成为针对男性不育症的新兴的生物学标志物和潜在的治疗靶点。
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