Role of Selenoprotein P in Male Fertility

描述（由申请人提供）：硒是维持男性生育力所需的必需膳食微量营养素。硒通过在其一级结构中含有化学计量量的硒（如硒代半胱氨酸）的硒蛋白发挥其生理活性。硒缺乏动物的附睾精子表现出丧失活力，并显示各种缺陷，包括线粒体鞘和鞭毛纤维的解体异常，我们的研究表明，缺陷依次出现在精子发生和睾丸后成熟强调硒在睾丸和附睾中的作用。睾丸和精子的硒含量高于其他组织，且在膳食硒缺乏时，睾丸维持硒含量的时间较其他组织长。因此，睾丸有一种机制，它可以有效地竞争动物体内的硒，以支持精子发育。硒蛋白P（SelenoproteinP，Se-P）是一种细胞外硒蛋白，占血浆中硒的绝大部分。我们已经产生了Se-P缺失小鼠，并且纯合雄性是不育的。硒磷缺乏小鼠睾丸硒水平极低，补硒不能提高睾丸硒水平。硒磷缺乏动物的精子细胞和附睾精子表现出硒缺乏的结构缺陷。我们的中心假设是硒磷提供硒到睾丸和附睾的特定细胞类型，以支持正常精子发育所需的硒蛋白合成。这项研究的具体目标是： 目标1：通过研究硒磷在睾丸和附睾中的定位，阐明硒磷在精子发生和睾丸后精子发育中的作用。 目的2：研究硒磷是否能为生精小管和附睾小管提供硒，以合成其他硒蛋白。 目的3：鉴定和定位睾丸和附睾中硒磷结合蛋白。 目的4：探讨硒磷缺乏小鼠精子缺陷的分子基础。

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.