Contraceptive agents to block sperm function in fertiliz

阻断精子受精功能的避孕药

• 批准号: 6611183
• 负责人: PAUL PRIMAKOFF
• 金额: $ 16.56万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-12 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6611183
• 关键词: Macaca; contraceptives; cooperative study; drug design /synthesis /production; drug screening /evaluation; fertility immunology; fertilization; gene targeting; histopathology; laboratory mouse; oral contraceptives; protein purification; sperm; sperm capacitation; spermicide; zona pellucida glycoproteins

DESCRIPTION (provided by applicant): This project focuses on the development of contraceptive agents to block two steps in fertilization. These agents will be orally available drugs that block either sperm binding to the egg's zona pellucida or sperm entry into the oviduct. To develop the first contraceptive drug, we will identify the sperm surface protein that enables sperm to bind to the egg's zona pellucida. Despite intensive investigation for the last 20 years, the sperm protein with this function remains unknown. In our recent research, we have developed two new mutant mouse lines in which the males are infertile and make sperm that fail to bind to the zona. The availability of these knockout mice, along with new genomic and proteomic technologies, provides us a completely novel approach to this problem. Having identified the sperm's zona binding protein, we will establish a high-throughput assay to screen inhibitors that block binding of the human zona binding protein to human ZP3. This high-throughput screen will be the key that allows subsequent contraceptive development with an industrial partner. For the second contraceptive agent, the starting point will be one of our mouse lines that carries a deletion of the sperm adhesion protein fertilin a. Male mice lacking fertilin a produce sperm that fail to enter the oviduct. We will test the hypothesis that sperm adhesion to the uterine or uterotubal junction epithelium requires fertilin a and that this binding step results in a signal that makes sperm competent to enter the oviduct. We propose assays for fertilin a adhesion to the epithelium and for screening small molecule inhibitors of the adhesion that will cause sperm arrest in the uterus.

描述（由申请人提供）：本项目的重点是避孕药的开发 阻止受精的两个步骤。这些药物将是口服药物，可以阻断精子与卵子透明质膜的结合或精子进入输卵管。 为了开发第一种避孕药，我们将鉴定出精子表面蛋白，使精子能够结合到卵子的透明膜上。尽管在过去的20年里进行了深入的研究，但具有这种功能的精子蛋白仍然是未知的。在我们最近的研究中，我们开发了两种新的突变小鼠品系，其中雄性不育，精子不能与精子结合。这些基因敲除小鼠的可用性，沿着新的基因组学和蛋白质组学技术，为我们提供了一个全新的方法来解决这个问题。在鉴定了精子的ZP3结合蛋白后，我们将建立一种高通量测定来筛选阻断人ZP3结合蛋白与人ZP3结合的抑制剂。这种高通量筛选将是与工业合作伙伴进行后续避孕开发的关键。 对于第二种避孕药，起点将是我们的一个小鼠品系，它携带了精子粘附蛋白fertilin a的缺失。缺乏受精素a的雄性小鼠产生的精子不能进入输卵管。我们将检验精子粘附到子宫或子宫输卵管交界处上皮需要受精素a，并且该结合步骤导致使精子有能力进入输卵管的信号的假设。我们建议测定受精素粘附上皮细胞和筛选小分子抑制剂的粘附，将导致精子在子宫内被捕。