Gamete surface metalloproteinases as contraceptive targets

描述（由申请人提供）：该项目的重点是确定一个表面 金属蛋白酶，特别是在精子或卵子上表达的，是受孕所必需的， 开发一种避孕剂，作为这种金属蛋白酶的特异性抑制剂。 金属蛋白酶抑制剂目前被用作药物，并且正在开发更多的药物来治疗各种人类疾病。在我们的研究中，我们最近有两个发现，作为这个建议的两个目标的基础。 具体目标1。开发一种金属蛋白酶抑制剂作为避孕药，阻断精子特异性ADAM蛋白酶（测试酶）的功能。我们已经发现，有一个亚家族的亚当家族的蛋白质称为测试酶。这些蛋白质具有金属蛋白酶共有活性位点，表明它们具有酶活性;它们的表达仅限于睾丸。 我们将检验这一假设，即测试酶在精子发育、成熟或精子功能中具有所需的作用，或者可能不止一种作用。 然后，我们将继续发展一种金属蛋白酶抑制剂，阻断测试酶的活性，并可用作避孕药。 具体目标2。开发一种金属蛋白酶抑制剂作为避孕药，阻止精子-卵子融合。我们还发现，有一个金属蛋白酶，显然需要哺乳动物精卵融合，目前在精子或卵子表面。 在目标2中，我们提出鉴定金属蛋白酶活性。我们将测试它是否是卵子或精子上的ADAM蛋白酶或基质金属蛋白酶（MMP）。如果蛋白酶是精子ADAM（即，目标1和目标2将相交。一旦确定了一种独特的金属蛋白酶，我们将测试组织特异性，并继续开发一种药物，作为该特定金属蛋白酶活性的抑制剂。

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.