MALE CONTRACEPTIIVES ACTING ON SPERM SURFACE TARGETS

作用于精子表面目标的男性避孕药

• 批准号: 6272248
• 负责人: Diana G Myles
• 金额: $ 16.26万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 1999-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6272248
• 关键词: Macaca fascicularis; antigen antibody reaction; autoantibody; blood testis barrier; cell adhesion molecules; contraceptives; drug screening /evaluation; epididymis; epitope mapping; fertility immunology; immunization; laboratory mouse; male; orchitis; sperm; vaccine development; vaccines

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.

该提案的重点是开发一种新的避孕方法 男人。该项目始于我们以前的发现，即 具有精子表面蛋白的雄性啮齿动物会导致两种作用： 抗植物抗体与附睾或精子中的精子结合 完全从附睾中消除，导致不育。在这个 我们建议使用啮齿动物研究来定义这些机制 两种现象并开发出获得每种效果的最佳方案。 然后，这些免疫协议将在猴子中进行测试以确定 如果它们影响灵长类动物的精子并诱发不育。同时，一个新的 将测试旨在引起男性避孕方法的方法 细胞细胞的破坏（通过免疫或药理手段） 睾丸中的相互作用，从而阻止了精子的发育。 我们的第一个目的是系统地优化免疫条件 在小鼠中，通过改变四个变量：选择抗原，辅助，剂量和 管理途径。小鼠将首先评估抗体 结合附睾精子或附睾精子丧失。这 免疫的雄性小鼠也将在存在的存在或 附睾炎可能相对最小或没有特异性 四个变量之间的选择。导致的最佳协议 附睾或射精中的抗体结合的精子将被测试。 精子在体外受精和体内的功能 免疫小鼠的生育能力。然后将测试有效的协议 在雄猴中。导致附子损失的最佳方案 小鼠中的精子将用于研究这种损失的机制并进行了测试 确定在雄性猴子中是否会消除附睾精子。 如果 获得避孕功效，但存在炎症，我们将 测试肽免疫原专门设计用于生产无需的抗体 炎症反应。我们还将研究早期生殖细胞以识别 细胞粘附分子出现在血液测缸屏障外，并且 因此，受到抗体或药理剂的抑制作用， 这不必越过障碍。