Role of Selenium in Development and Health

硒在发育和健康中的作用

• 批准号: 8157171
• 负责人: Dolph Hatfield
• 金额: $ 38.29万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8157171
• 关键词: Development; Health; Role; Selenium

Selenium is an essential micronutrient in the diet of humans and other mammals. Many health benefits have been attributed to selenium that include preventing various forms of cancer (e.g., colon cancer, prostate cancer, lung cancer and liver cancer), heart disease and other cardiovascular and muscle disorders, inhibiting viral expression, delaying the progression of acquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus (HIV)-positive patients, slowing the aging process, and having roles in mammalian development, including male reproduction and immune function. Numerous human clinical trails have been undertaken in recent years to assess the role of this element in cancer prevention, delaying the progression of AIDS, etc., at a cost of billions of dollars, but little is known about the mechanism of how selenium acts at the metabolic level in mammals to exert these many health benefits. We have proposed that the health benefits of selenium are due largely to its presence in selenoproteins as the selenium-containing amino acid, selenocysteine (Sec). Our program therefore focuses on: 1) developing mouse models to assess the role of selenium and selenoproteins in cancer prevention and development, 2) characterizing and elucidating the function of various selenoproteins and their roles in cancer prevention and development, and 3) identifying the means by which Sec is biosynthesized and incorporated into protein. The project discussed herein examines our research on the development of various mouse models for determining the role of selenium in cancer, cancer prevention and development. In the past several years, we have focused on completing our studies on characterizing mouse models: 1) that knockout the Sec tRNA gene (designated Trsp) and consequently result in the loss of selenoprotein expression in (a) T cells, (b) macrophage, (c) epidermal skin tissue, and (d) liver, and subsequent rescue or partial rescue of selenoprotein expression with a wild-type or mutant Trsp transgene. Our direction of focus in this project has shifted in the past year almost totally towards generating mouse models that deal with the role of selenoproteins in the progression of cancer and the targeted removal of individual selenoproteins instead of knocking out all selenoproteins through the removal of Trsp. In an earlier fiscal year, we completed our study on examining the molecular mechanism of selenoproteins in cell immunity and in the past year, we emphasized providing sufficient mice to complete a collaborative study with Dr. Melinda Beck in determining the effects of deficient, adequate, and supplemental levels of selenium intake on the immune response mediated by T cells in mice that do not express selenoproteins in T cells or express only the critical, housekeeping selenoproteins (but not the non-essential, stress-related selenoproteins). We have continued a study on targeting the removal of only thioredoxin reductase 1 (TR1) and/or glutathione peroxidase 4 (GPx4) in various tissues to examine the role of these two essential selenoproteins in several organs and tissues. Loss of GPx4 in epidermal tissue (designated skin herein) virtually mimicked the loss of all selenoproteins with the exception that the mice recover after day 10, when they routinely died in Trsp knockout mice, and appear to live a virtually normal life. The GPx4 knockout mice had alopecia along with a flaky and fragile skin and histological studies revealed epidermal hyperplasia along with changes in hair follicle appearance. These observations demonstrate a prior unknown role of GPx4 in cutaneous development providing further evidence that this selenoprotein has many essential functions in cell development. The targeted removal of TR1 in skin did not appear to have any alteration in phenotype. In our in vivo colon carcinogenesis study, we were able to demonstrate that Sep15 knockout mice, compared to wild type or heterozygote littermate controls, appeared to be protected against azoxymethane-induced formation of pre-neoplastic lesions (aberrant crypt foci). Furthermore, using microarrays as well as real-time rtPCR analysis of the colonic mucosa showed that guanylate-binding protein 1 was highly up-regulated in Sep15 knockout mice. The possible connection between this interferon-gamma-regulated protein and the 15kDa selenoprotein in colon cancer will be investigated in future experiments. In addition, the possible influence of dietary selenium in our colon cancer model using Sep15 knockout mice will be further elucidated. Furthermore, our other mouse study model, which involved using liver TR1 deficient mice exposed to the liver carcinogen, diethylnitrosamine, (DEN), came to fruition in the past year. We found that liver-specific TR1 knockout mice developed tumors (hepatic adenomas, hepatic carcinomas and hepatocholangiocellular adenomas) much more readily than control mice. 16 of 18 knockout mice developed tumors compared to 2 of 19 control mice. In addition, we found an upregulation of Nrf2-modulated genes in the TR1 deficient livers, including several of the glutathione transferases and the selenoprotein, glutathione peroxidase 2, which was even further upregulated in tumors.

硒是人类和其他哺乳动物饮食中必不可少的微量营养素。 Many health benefits have been attributed to selenium that include preventing various forms of cancer (e.g., colon cancer, prostate cancer, lung cancer and liver cancer), heart disease and other cardiovascular and muscle disorders, inhibiting viral expression, delaying the progression of acquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus (HIV)-positive patients, slowing the aging process, and having roles in哺乳动物发育，包括男性繁殖和免疫功能。近年来，已经进行了许多人类的临床踪迹，以评估该元素在预防癌症中的作用，延迟艾滋病的进展等，以数十亿美元的成本，但对哺乳动物中代谢水平的代谢水平如何施加这些许多健康益处的机制知之甚少。 我们已经提出，硒的健康益处主要是由于其在硒蛋白中作为含硒的氨基酸，硒代半胱氨酸（SEC）的存在。因此，我们的程序侧重于：1）开发小鼠模型来评估硒和硒蛋白在癌症预防和发育中的作用，2）表征和阐明各种硒蛋白的功能及其在预防癌症预防和发育中的作用，以及3）确定SEC通过生物合成并掺入蛋白质中的方法。本文讨论的项目研究了我们对确定硒在癌症，预防癌症和发育中作用的各种小鼠模型的开发的研究。 In the past several years, we have focused on completing our studies on characterizing mouse models: 1) that knockout the Sec tRNA gene (designated Trsp) and consequently result in the loss of selenoprotein expression in (a) T cells, (b) macrophage, (c) epidermal skin tissue, and (d) liver, and subsequent rescue or partial rescue of selenoprotein expression with a wild-type or mutant Trsp转基因。在过去的一年中，我们的重点方向几乎完全朝着产生硒蛋白在癌症进展中的作用和靶向去除单个硒蛋白的作用的小鼠模型，而不是通过去除TRSP来淘汰所有硒蛋白。 在早期的财政上，我们完成了研究研究细胞免疫中硒蛋白的分子机制的研究，在过去的一年中，我们强调提供足够的小鼠来完成与梅琳达·贝克（Melinda Beck）博士确定不足，足够和补充质量抗性细胞中脑介导或补充细胞中的脑中临时或补充细胞中的梅尼西亚（T）的效果的协作研究，该细胞中的细胞中的细胞中的细胞中的细胞均不高，并不是在确定梅尼（Selenium）的效果。管家硒蛋白（但不是与不必要的，与压力有关的硒蛋白）。我们继续进行一项研究，该研究仅针对除硫氧还蛋白还原酶1（TR1）和/或谷胱甘肽过氧化物酶4（GPX4）中的去除，以检查这两种必需硒蛋白在几个器官和组织中的作用。表皮组织（本文指定的皮肤）中GPX4的损失实际上模仿了所有硒蛋白的丧失，但第10天后，小鼠通常死于TRSP敲除小鼠，并且似乎过着正常的寿命。 GPX4基因敲除小鼠的脱发和脆弱和脆弱的皮肤和组织学研究揭示了表皮增生以及毛囊外观的变化。这些观察结果表明，GPX4在皮肤发育中的先前未知作用提供了进一步的证据，表明该硒蛋白在细胞发育中具有许多基本功能。皮肤中TR1的靶向去除似乎在表型中没有任何改变。 在我们的体内结肠致癌研究中，我们能够证明，与野生型或杂合子同窝状对照相比，Sep15基因敲除小鼠似乎受到保护，从而免受硫烷甲烷诱导的持续性塑性塑性病变的形成（异常隐性灶）。此外，使用微阵列以及对结肠粘膜的实时RTPCR分析表明，在SEP15敲除小鼠中，鸟烯基结合蛋白1高度上调。将在未来的实验中研究这种干扰素γ调节的蛋白与结肠癌中15KDA硒蛋白之间的可能联系。此外，将进一步阐明饮食中硒在我们的结肠癌模型中的可能影响。此外，我们的其他小鼠研究模型涉及使用暴露于肝癌的肝脏TR1缺乏小鼠，二乙基硝基胺（DEN）在过去一年中实现了。我们发现，肝脏特异性的TR1敲除小鼠比对照小鼠更容易发出肿瘤（肝腺瘤，肝癌和肝胆管细胞腺瘤）。与19例对照小鼠中有2只相比，有18只敲除小鼠中有16只患有肿瘤。此外，我们发现TR1缺乏肝脏中NRF2调节的基因的上调，包括几种谷胱甘肽转移酶和硒蛋白，麦芽磷脂过氧化物酶2，在肿瘤中进一步上调。