Male Nonhormonal Contraception Via Sphingolipid Biosynthesis Inhibitors

描述（由申请人提供）：避孕方法使用激素来阻止生殖细胞成熟或通过手术或屏障干扰精子-卵子融合。在实行计划生育的约6亿对夫妇中，男性仅限于使用避孕套和输精管结扎，但男性占所有避孕措施的三分之一。由于现有男性避孕方法的缺陷，研究人员试图为男性开发额外的可逆避孕方法。最广泛测试的方法是使用外源性睾酮来抑制促性腺激素的释放，从而剥夺精子发生所需的睾丸信号。缺点包括观察到一些男性对激素干扰没有反应，无精子症的发病延迟3个月；因此，需要发展非激素的男性避孕方法。研究人员注意到，天生缺乏鞘糖脂（GSL）的雄性小鼠不育，但在所有其他方面都是正常的。这表明GSL生物合成抑制剂可能为非激素男性避孕方法的发展提供了新的范例。研究表明，用一种鞘脂模拟物米格司他治疗雄性小鼠会导致不育，这种效果在停药后是完全可逆的。这种模拟物被批准用于人类治疗戈谢病，抑制葡萄糖基转移酶，一种负责神经酰胺到脑苷的生物合成转化的酶。经过处理的小鼠的精子表现出异常的形态和缺乏顶体抗原，但具有遗传能力。不幸的是，由于未知的原因，这种分子在人类或高等物种中没有类似的作用。为了更好地理解鞘糖脂抑制在精子发生中的作用，我们已经确定了抑制GSL产生或导致GSL消耗的化合物，并将测试它们在体内的抗生育潜力。本项目的目的是探讨鞘糖脂生物合成抑制剂引起可逆性男性不育的能力。

DESCRIPTION (provided by applicant): Contraceptive methods use hormones to prevent germ cell maturation or interfere with sperm-egg fusion via surgery or barriers. Of the ~600 million couples that employ family planning, males are limited to condoms and vasectomies, yet men account for one-third of all contraception. Because of drawbacks to current existing male methods researchers have attempted to develop additional reversible contraceptives for men. The most extensively tested approach utilizes the administration of exogenous testosterone to suppress gonadotropin release thereby depriving the testes of the signals required for spermatogenesis. Drawbacks include the observation that some men fail to respond to hormonal interference and there is a 3-month delay in the onset of azoospermia; therefore, the development of non-hormonal approaches to male contraception is needed. Researchers have noted that male mice inherently devoid of glycosphingolipids (GSL) are sterile but normal in all other aspects. This suggests that inhibitors of GSL biosynthesis may provide a new paradigm for the development of non-hormonal methods of male contraception. Studies have demonstrated that male mice are rendered infertile when treated with miglustat, a sphingolipid mimic, an effect which is fully reversible after discontinuation. This mimic, approved for use in humans for the treatment of Gaucher's disease, inhibits glucosyl transferase, an enzyme responsible for the biosynthetic conversion of ceramide to cerebroside. Sperm from treated mice display abnormal morphologies and lack acrosome antigens but are genetically competent. Unfortunately, for unknown reasons this molecule does not have similar effects in humans or higher species. To better understand the role of glycosphingolipid inhibition in spermatogenesis, we have identified compounds that either inhibit the production or cause the depletion of GSL and will test their in vivo anti-fertility potential. The goal of this project is to explore the ability of glycosphingolipid biosynthesis inhibitors to cause reversible male infertility.