男性不育约占不孕不育的50%，近3/4的男性不育病因不明。精子活力低下是男性不育的关键因素，维持精子中段游离钙和线粒体的功能是提高精子活力所必需。已知钙调磷酸酶（CaN）缺失可促进线粒体改变，CaN缺失或其抑制剂FK506均可使精子中段僵化致雄鼠不育，但机制不明。我们曾发现FK506与FKBP12或FKBP12.6（F12.6）结合均可抑制CaN活性，F12.6可选择性地与RyR2结合调控钙离子的释放，预实验提示精子特异性CaN优先结合F12.6-FK506复合物，敲除F12.6基因可明显逆转FK506所致的不育。本课题拟利用F12.6基因敲除鼠，旨在探讨F12.6在FK506所致雄鼠不育中的作用，通过检测精子胞内钙离子、CaN活性、RyR2磷酸化、线粒体超微结构等改变阐明其机制。我们还将观察FK506的非免疫抑制类似物能否逆转FK506所致的雄鼠不育，为男性不育治疗药物的开发提供新思路。

Male infertility accounts for about half of human infertility, however, nearly 3/4 of pathogenesis in male infertility is still unknown, there are very few studies concentrated on the causes and therapies of male infertility. It is reported that low sperm motility is a key factor in male infertility, it is necessary to maintain the regulation of free calcium in sperm midpiece and maintain the high activity of sperm mitochondria for improving sperm motility. Studies have shown that deficiency of CaN lead to mitochondrial changes, and CaN deletion or its inhibitor FK506 both lead to spermatozoa with a rigid midpiece, but the mechanism is unknown. We have found that FK506 binding to FKBP12.6 (F12.6) or FKBP12 and inhibit the activity of CaN, F12.6 selectively bind to RyR2 to regulate the release of calcium ions. In the preliminary experiment, it was found that sperm-specific CaN preferentially binds to F12.6-FK506 complex, and deletion of F12.6 gene significantly reverse the FK506-induced male infertility. In this study, F12.6 gene knockout mice were used to explore the role of F12.6 in male infertility induced by FK506, and the mechanism was clarified by detecting changes in calcium ions, CaN activity, RyR2 phosphorylation and mitochondrial ultrastructure in sperm cells. In addition, we will observe whether the non-immunosuppressive analogues of FK506 can reverse the male infertility induced by FK506, so as to provide a new idea for the development of treatment drugs for male infertility.