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）：该项目着重于避孕药的发展 代理人阻止受精的两个步骤。这些药物将是口服的药物，可以阻止精子与卵的Zona pellucida结合或精子进入输卵管。 为了开发第一种避孕药，我们将鉴定精子表面蛋白，该蛋白使精子能够结合卵的Zona pellucida。尽管过去20年进行了深入研究，但具有该功能的精子蛋白仍然未知。在最近的研究中，我们开发了两种新的突变小鼠系，其中雄性不育，使精子无法与Zona结合。这些敲除小鼠的可用性以及新的基因组和蛋白质组学技术为我们提供了一种完全新颖的方法来解决这个问题。在确定了精子的Zona结合蛋白之后，我们将对筛选抑制剂建立高通量测定法，该测定法阻断人Zona结合蛋白与人ZP3的结合。这个高通量屏幕将是允许与工业合作伙伴进行后续避孕开发的关键。 对于第二种避孕剂，起点将是我们的小鼠系之一，它携带了精子粘附蛋白肥料a的缺失。缺乏肥料A的雄性小鼠无法进入输卵管。我们将检验以下假设：精子粘附对子宫或子宫内结上皮需要受精蛋白A，并且该结合步骤会产生一个信号，使精子能够有能力进入Oviduct。我们提出了对上皮粘附的测定法，并筛选粘附的小分子抑制剂，这将导致子宫中的精子停滞。