男性不育症迄今仍有37-58%的患者病因不明！其病因学及新诊断方法的研发仍面临艰巨挑战。前期工作中发现三种功能未知，可能属丝氨酸蛋白酶家族，在睾丸特异性表达的基因（Prss37、54、55）被剔除后，三种小鼠均表现雄性不育或生殖能力显著下降！其中，Prss37的缺失造成精卵识别/结合及精子在体迁移障碍；Prss54缺失的精子不能穿过透明带使卵受精；剔除Prss55的精子亦表现出精卵结合的障碍。同时发现在98例所谓“不明原因男性不育（UMI）”精液样本中PRSS37蛋白水平较正常显著下降甚至消失！据此我们有理由认为这三种可能的丝氨酸蛋白酶为小鼠精子使卵受精所必需，其表达低下或功能缺失可能是UMI发生的重要原因。本项目将围绕这三种蛋白质的性质、生理功能、作用机制及其在UMI发生中的作用展开系统研究。预期结果将对认识新基因功能、解析UMI病因、开发新型诊断、治疗及节育手段具有重要理论和应用价值。

Male infertility of unknown origin accounts for 37-58% of infertility caused by male factors. Therefore, there is still a big challenge in understanding its pathogenesis and developing new diagnostic approach. Our group has previously found that respective disruption of three probable serine proteinases with unknown function but specifically expressed in mouse testis leads to male infertility or imparied fertility. Further observations show that Prss37-deficency leads to the defects in sperm-egg recognition/binding and sperm migration from uterus to oviduct. Prss54 knockout sperm fail to penetrate zona pellucida. Prss55-deficient sperm exhibit similar phenotype with Prss37 null sperm. Most importantly, we found that PRSS37 protein level was dramatically decreased in 98 semen samples from the patients with unexplained male infertility (UMI), and even undetectable in 7 out of these samples. Our data indicate that these three novel serine proteinases are indispensible for sperm fertilization in mice. The defects in the expression or function of these proteins may be causative for UMI patients. The current project will focus on characterizing these novel proteins, deciphering their biological function and molecular mechanism by utilizing the advantage of mutant mouse models, exploring their causative role in the development of UMI. We believe that our expecting results will be greatly helpful in understanding novel gene function and pathogenesis of UMI, and in developing new approaches of diagnosis, treatment for UMI patients, and novel strategy for birth control.