Role of Selenoprotein P in Male Fertility

描述（由申请人提供）：硒是维持男性生育能力所需的必需膳食微量营养素。硒通过在其初级结构中含有一定量硒的硒蛋白（如硒半胱氨酸）发挥其生理活性。缺硒动物的附睾精子表现出运动能力丧失和各种缺陷，包括线粒体鞘异常和鞭毛纤维紊乱；我们的研究表明，这些缺陷在精子发生和睾丸后成熟过程中依次出现，强调了硒在睾丸和附睾中的作用。饲粮缺硒时，睾丸和精子的硒含量高于其他组织，且睾丸维持硒含量的时间较其他器官长。因此，睾丸有一种机制，它与动物体内的硒有效竞争，以支持精子的发育。硒蛋白P （seloprotein P, Se-P）是一种细胞外硒蛋白，占血浆中硒的大部分。我们已经培育出Se-P缺失小鼠，纯合子雄性不育。硒磷缺失小鼠的睾丸硒水平极低，硒的补充没有提高硒的水平。硒磷缺失动物的精子和附睾精子表现出缺硒的结构缺陷。我们的中心假设是硒- p为睾丸和附睾的特定细胞类型提供硒，以支持正常精子发育所需的硒蛋白合成。本研究的具体目的是：

DESCRIPTION (provided by applicant): Selenium is an essential dietary micronutrient required to maintain male fertility. Selenium exerts its physiological activity through selenoproteins that contain stochiometric amounts of selenium, as selenocysteine, in their primary structure. Epididymal spermatozoa of selenium deficient animals exhibit a loss of motility and display various defects including abnormalities of the mitochondrial sheath and disorganization of the flagellar fibers; our studies demonstrate the defects appear sequentially during spermiogenesis and post-testicular maturation underscoring roles for selenium in both the testis and epididymis. Selenium concentrations of the testis and spermatozoa are higher than other tissues, and the testis maintains its selenium content longer than other organs during dietary selenium deficiency. Thus the testis has a mechanism with which it competes effectively for selenium within the animal to support sperm development. Selenoprotein P (Se-P) is an extracellular selenoprotein that accounts for most of the selenium in plasma. We have produced Se-P null mice and the homozygous males are infertile. Testis selenium levels of Se-P null mice are extremely low and not elevated by selenium supplementation. Spermatids and epididymal spermatozoa of Se-P null animals exhibit structural defects of selenium deficiency. Our central hypothesis is that Se-P provides selenium to specific cell types of the testis and epididymis to support selenoprotein synthesis required for normal sperm development. The specific aims of this study are: Aim 1: To elucidate the potential roles of Se-P in spermiogenesis and post-testicular sperm development by defining its localization in the testis and epididymis. Aim 2: To determine if Se-P provides selenium to the seminiferous and epididymal tubules for biosynthesis of other selenoproteins. Aim 3: To identify and localize Se-P-binding proteins in the testis and epididymis. Aim 4: To determine the molecular basis for sperm defects in Se-P null mice.