MALE CONTRACEPTIIVES ACTING ON SPERM SURFACE TARGETS

这项提案的重点是开发一种新的避孕方法 男人。该项目始于我们之前发现的免疫接种 携带精子表面蛋白的雄性啮齿动物会产生两种影响中的一种： 抗精子抗体与附睾中的精子或精子结合 从附睾处完全消失，导致不育。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，并制定获得每一种效果的最佳方案。 这些免疫方案随后将在猴子身上进行测试，以确定 如果它们影响灵长类的精子并导致不育。同时，一个新的 男性避孕方法将进行测试，旨在导致 细胞-细胞的破坏(通过免疫或药物手段) 睾丸中的相互作用，从而阻碍精子的发育。 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、佐剂、剂量和 管理路线。首先将对小鼠进行抗体评估 与附睾体精子结合或附睾体内精子丢失。这个 免疫的雄性小鼠也将被打分，看是否存在炎或 附睾炎可能相对轻微或不伴有特殊的附睾炎 在四个变量中进行选择。最优协议(S) 附睾液或射精液中的抗体结合的精子将进行检测 精子在体外受精和体内发挥作用的能力 免疫小鼠的生育力。然后将测试一个有效的协议 在雄性猴子身上。导致附睾丧失的最佳治疗方案 老鼠的精子将被用来研究这种丢失的机制并进行测试 以确定雄性猴子的附睾精子是否会被消除。如果 避孕有效，但存在炎症，我们会 测试多肽免疫原，专门设计用于产生抗体，而不需要 一种炎症反应。我们还将研究早期生殖细胞，以确定 细胞黏附分子存在于血-睾丸屏障外 因此容易受到抗体或药理学试剂的抑制， 这将不需要越过障碍。

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.