MALE CONTRACEPTIIVES ACTING ON SPERM SURFACE TARGETS

这项建议的重点是开发一种新的避孕方法， 男人该项目始于我们先前的发现， 雄性啮齿类动物精子表面蛋白导致两种效果之一： 抗精子抗体与附睾中的精子结合，或者精子 从附睾中完全排出导致不孕在这 我们建议使用啮齿动物研究来确定这些机制， 两种现象，并制定最佳协议，以获得每一个效果。 这些免疫方案将在猴子身上进行测试， 如果它们影响灵长类动物精子并导致不育同时，一个新的 男性避孕方法将被测试，旨在引起 细胞-细胞破坏（通过免疫学或药理学手段 睾丸中的相互作用，从而阻止精子发育。 我们的首要目标是系统地优化免疫条件 通过改变四个变量：抗原的选择、佐剂、剂量和 给药途径。首先对小鼠进行抗体评估 与附睾精子结合或附睾精子丢失。的 免疫的雄性小鼠也将对睾丸炎或 附睾炎可能相对轻微或不存在， 四个变量中的选择。最佳协议，导致 将对附睾或射精中的抗体结合精子进行检测， 精子在体外受精和体内的功能 免疫小鼠的生育力。然后将测试有效的方案 在雄性猴子身上。导致附睾缺失的最佳方案 小鼠的精子将被用来研究这种损失的机制， 以确定雄性猴子的附睾精子是否会被清除。 如果 避孕效果获得，但炎症存在，我们将 测试肽免疫原，专门设计用于产生抗体， 炎症反应我们还将研究早期生殖细胞， 细胞粘附分子存在于血-睾丸屏障外， 因此受到抗体或药理学试剂的抑制， 不需要越过屏障

This proposal is focused on developing a new contraceptive method for men. The project begins with our previous finding that immunization of male rodents with sperm surface proteins leads to either of two effects: anti-sperm antibody becomes bound to sperm in the epididymis or sperm are completely eliminated from the epididymis, leading to infertility. In this project we propose to use rodent studies to define the mechanisms of these two phenomena and to develop optimal protocols for obtaining each effect. These immunization protocols will then be tested in monkeys to determine if they affect primate sperm and induce infertility. Simultaneously, a new approach to male contraception will be tested that is designed to cause the disruption (by immunological or pharmacological means) of cell-cell interactions in the testis, thus blocking sperm development. Our first aim is to systematically optimize immunization conditions in mice by altering four variables: choice of antigen, adjuvant, dose and route of administration. The mice will first be evaluated for antibody bound to epididymal sperm or loss of sperm in the epididymis. The immunized male mice will also be scored for presence of orchitis or epididymitis which may be relatively minimal or absent with specific choices among the four variables. The optimal protocol(s) that leads to antibody-bound sperm in the epididymis or ejaculate will be tested for the ability of the sperm to function in vitro fertilization and in vivo fertility of immunized mice. An efficacious protocol will then be tested in male monkeys. The optimal protocol that leads to loss of epididymal sperm in mice will be used to study the mechanism of this loss and tested to determine if epididymal sperm will be eliminated in male monkeys. If contraceptive efficacy is obtained, but inflammation is present, we will test peptide immunogen specifically designed to produce antibodies without an inflammatory response. We will also study early germ cell to identify cell adhesion molecules present outside the blood-testis barrier and therefore subject to inhibition by antibodies or pharmacological agents, that will not have to cross the barrier.