Physiological effects of altered Se transport and Se tissue distribution in selenoprotein P knock out mice - studies on the impact of gender on the phenotype

硒蛋白 P 敲除小鼠硒转运和硒组织分布改变的生理效应——性别对表型影响的研究

• 批准号: 5425310
• 负责人: Professor Dr. Lutz Schomburg
• 金额: --
• 依托单位: Institut für Biochemie und Molekularbiologie (IBMB)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2004
• 资助国家: 德国
• 起止时间: 2003-12-31 至 2006-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5425310?language=en
• 关键词: Physiological; effects; altered; Se; transport

Selenium (Se) is mainly contained in plasma within a soluble glycoprotein, i.e. selenoprotein P (SePP). We generated viable SePP-KO mice by targeted disruption of the SEPP locus. These mice display a complex phenotype with respect to growth, survival, fitness, fertility, etc. SePP-KO mice are mainly characterized by an altered Se-distribution among the organs and by disturbed expression of the other selenoproteins indicating that SePP functions as a Se-carrier and -transporter. The phenotype displays a simple gene-dose relationship. Moreover, the major effects emerged in a gender-specific manner. Here, the most striking examples were male infertility and spontaneous fatalities that we observed in around 30% of male SePP-KO mice. Likewise male SePP-KO mice displayed more pronounced growth defects, reduced fat mass and more pronounced ataxia. These findings point to an unresolved issue, i.e. sex-specific effects of Se that have rarely received major attention, yet. Thus we plan to compare the phenotype of male and female SePP-KO mice in detail. Are the endocrine glands affected differently in male and female SePP-KO mice? Are there gender-specific differences in gene expression that ameliorate the female phenotype? Or do female-specific hormones/hormone-levels protect from the adverse effects that arise when the Se supply is limiting? Since there are also hints from clinical medicine describing gender-specific effects of Se in pathophysiological conditions, we believe that these studies will be suited to clarify some of the underlying mechanisms.

硒 (Se) 主要包含在血浆中的可溶性糖蛋白中，即硒蛋白 P (SePP)。我们通过靶向破坏 SEPP 基因座产生了可存活的 SePP-KO 小鼠。这些小鼠在生长、生存、健康、生育力等方面表现出复杂的表型。SePP-KO 小鼠的主要特征是器官中硒分布的改变以及其他含硒蛋白的表达紊乱，表明 SePP 充当硒载体和转运蛋白。表型显示出简单的基因-剂量关系。此外，主要影响是以特定性别的方式出现的。在这里，最引人注目的例子是我们在大约 30% 的雄性 SePP-KO 小鼠中观察到的雄性不育和自发死亡。同样，雄性 SePP-KO 小鼠表现出更明显的生长缺陷、脂肪量减少和更明显的共济失调。这些发现指出了一个尚未解决的问题，即硒对性别的影响目前还很少受到关注。因此，我们计划详细比较雄性和雌性 SePP-KO 小鼠的表型。雄性和雌性 SePP-KO 小鼠的内分泌腺受到的影响是否不同？基因表达是否存在改善女性表型的性别特异性差异？或者女性特有的激素/激素水平是否可以防止硒供应有限时产生的不利影响？由于临床医学也有一些线索描述了硒在病理生理条件下的性别特异性影响，我们相信这些研究将适合阐明一些潜在的机制。