男性生育依赖于睾丸产生优质的精子。睾丸精子发生包括精原细胞有丝分裂、精母细胞减数分裂和精子形成三个阶段。其中，精子形成是圆形精子细胞经细胞分化和形态变化形成精子的过程。该过程异常将直接影响精子数量、形态和运动能力，造成男性不育。在肥胖致弱/畸精子症的蛋白组学研究中，我们发现一个内质网蛋白VAPA可能与精子质量相关。进一步研究发现VAPA在睾丸组织高表达，且主要表达于精子发生晚期的精子细胞中。通过构建生精细胞特异的Vapa基因敲除小鼠，我们初步发现该基因敲除小鼠表现为雄性不育，其精子形成异常，造成严重少弱畸形精子症的表型。因此，本课题将从基础和临床两方面，探索VAPA参与精子形成、影响精子质量的分子机制，明确人精子VAPA蛋白含量与少弱畸精子症发生的相关性，以及引起人精子VAPA含量异常的可能致病因素和有效治疗方法，从而为部分男性不育的病因学诊断和治疗提供必要的理论基础和充分的实验依据。

Male fertility depends on certain amounts of spermatozoa with sufficiently high quality produced in testis. Accordingly, Spermatogenesis in testis is a highly complex and specialized process consisting of spermatogonial mitosis，spermatocytic meiosis and spermiogenesis. Notably, spermiogenesis is the differentiational process by which haploid round spermatids complete an extraordinary series of events to become streamlined spermatozoa capable of motility. Defects in spermiogenesis is manifested as low sperm number, abnormal sperm morphology and poor motility, which are commonly observed in infertile males and genetically characterized as oligoasthenoteratozoospermia. Interestingly, in our previous research, differential proteomic analysis was performed on spermatozoa from obesity-associated astheno-teratozoospermia and an endoplasmic reticulum protein VAPA was verified declines in astheno-teratozoospermia which may contribute to the underlying sperm quality defects. Furthermore, we firstly found that VAPA was highly expressed in mouse testis, especially in the spermatids. In order to explore the particular function of VAPA in spermatids, a conditional knockout (CKO) mice model, which specific deleted Vapa gene in the germ cells, was established and preliminary experiments were performed. Comparing to the healthy males, the Vapa CKO males suffered from severe oligoasthenoteratozoospermia and therefore were infertility. Therefore, this applying project, combined fundamental research and clinical investigation, is focus on the mechanism of VAPA involving in spermiogenesis and resulting in sperm defects. It will contribute to illuminate the potential role of sperm VAPA expression in the cause of oligoasthenoteratozoospermia. Meanwhile, this applying project will also explore the possibly pathogenic factors and the effective therapies of male fertility that associated with sperm VAPA defects. Finally, it will contribute to improving the diagnosis and treatment of male infertility induced by spermiogenesis disorder.