Gamete surface metalloproteinases as contraceptive targets

配子表面金属蛋白酶作为避孕靶点

• 批准号: 6611184
• 负责人: Diana G Myles
• 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/6611184
• 关键词: Macaca fascicularis; contraceptives; cooperative study; drug design /synthesis /production; drug screening /evaluation; enzyme activity; fertility immunology; fertilization; laboratory mouse; metalloendopeptidases; protease inhibitor; sperm

DESCRIPTION (provided by applicant): This project is focused on identifying a surface metalloprotease, specifically expressed on sperm or eggs, that is essential for conception and developing a contraceptive agent that acts as a specific inhibitor of this metalloprotease. Metalloprotease inhibitors are currently used as drugs and more are being developed to treat a variety of human disorders. In our research we have recently made two discoveries that serve as the basis for each of the two aims of this proposal. Specific Aim 1. Develop a metalloprotease inhibitor as a contraceptive agent that blocks the function of sperm-specific ADAM proteases (testases). We have found that there is a subfamily of the ADAM family of proteins called the testases. These proteins have a metalloprotease consensus active site, indicating they have enzyme activity; their expression is confined to the testis. We will test the hypothesis that testases have a required role, or perhaps more than one role, in sperm development, maturation or in sperm function. We will then proceed toward development of a metalloprotease inhibitor that blocks testase activity and can be used as a contraceptive agent. Specific Aim 2. Develop a metalloprotease inhibitor as a contraceptive agent that blocks sperm- egg fusion. We also found that there is a metalloprotease, apparently required for mammalian sperm-egg fusion, present on either the sperm or the egg surface. In Aim 2 we propose to identify that metalloprotease activity. We will test if it is an ADAM protease or matrix metalloprotease (MMP) on the egg or the sperm. If the protease is a sperm ADAM (i.e., a testase), Aims 1 and 2 will intersect. Once a unique metalloprotease is identified, we will test for tissue specificity and proceed toward development of a drug that will act as an inhibitor for that specific metalloprotease activity.

描述（由申请人提供）：该项目的重点是识别表面 金属蛋白酶，专门在精子或卵上表达的金属蛋白酶，这对于构思和 开发一种避孕剂，该剂充当该金属蛋白酶的特定抑制剂。 金属蛋白酶抑制剂目前被用作药物，并且正在开发更多用于治疗各种人类疾病。在我们的研究中，我们最近进行了两个发现，这些发现是该提案两个目标中每个目标的基础。 具体目标1。开发金属蛋白酶抑制剂作为阻断精子特异性亚当蛋白酶功能（测试酶）功能的避孕剂。我们发现，亚当蛋白质家族的亚家族称为Tastass。这些蛋白质具有金属蛋白酶共识活性位点，表明它们具有酶活性。它们的表达仅限于睾丸。 我们将检验以下假设：测试酶在精子发育，成熟或精子功能中具有所需的作用，或可能多个作用。 然后，我们将继续开发可阻断睾丸蛋白活性的金属蛋白酶抑制剂，并可以用作避孕剂。 特定目标2。开发金属蛋白酶抑制剂作为阻断精子融合的避孕剂。我们还发现，存在于精子或卵表面上的哺乳动物精子融合所需的金属蛋白酶。 在AIM 2中，我们建议确定金属蛋白酶活性。我们将测试它是鸡蛋还是精子上的Adam蛋白酶或基质金属蛋白酶（MMP）。如果蛋白酶是精子亚当（即静态），则目标1和2将相交。一旦确定了唯一的金属蛋白酶，我们将测试组织特异性，并继续开发该药物，该药物将充当该特定金属蛋白酶活性的抑制剂。