Selenoproteins and Selenium-dependent Redox Signaling Alter Diabetes Risk

硒(Se)是哺乳动物体内的一种必需的微量营养素。 含硒半胱氨酸的蛋白质。这组硒蛋白由50多种蛋白质组成 然而，它们都是硒蛋白，似乎都有助于抗氧化和氧化还原调节。 硫醇氧化还原酶的形式。人类硒蛋白质组由25种硒蛋白组成，它们是 参与氧化应激保护、信号转导以及折叠、修饰和 蛋白质的调节。硒蛋白的表达取决于膳食中的硒含量。有趣的是，最近 临床试验表明，硒的过度营养可能显著增加患2型糖尿病的风险。 发展。随后涉及小鼠模型的研究表明，低和高硒摄入量是 两者都与2型糖尿病样表型有关；然而，这一特殊机制 这一现象尚未得到调查。世界不同地区的特点是 土壤中硒含量的变化以及与之相关的膳食硒含量的变化。世界上许多地区 美国是富硒国家，美国人口的特点是富硒。 因此，这可能会增加患糖尿病的风险。此外，富硒的使用 这些地区的膳食补充剂可能会对健康产生负面影响，并增加 糖尿病。这个项目的目标是研究硒和硒蛋白在氧化还原调节中的作用。 葡萄糖的动态平衡。中心假设是，硒调节硒蛋白的合成，在 反过来，改变氧化还原动态平衡，并影响胰岛素信号通路。具体地说，福梅科博士 将确定补硒对氧化还原依赖的胰岛素信号的影响。这项工作将是 在两个特定目标的指导下：(1)确定硒依赖型2型糖尿病的发病机制 以及(2)评估硒蛋白在过氧化氢信号转导和相关调控中的作用 葡萄糖的动态平衡。这些目标将使用生化和细胞相结合的方法来实现 生物学研究和动物模型。拟议的研究符合内布拉斯加州中心的使命 通过饮食分子(NPOD)预防肥胖疾病，并将有助于确定机制 与硒微量营养素相关的糖尿病的发展。NPOD支持、设施和指导将允许 Fomeko博士将这个项目推向一个独立的R01奖项，并实现他的长期 硒生物学的研究目标。

Selenium (Se) is an essential micronutrient in mammals tiiat exerts its function in the context of selenocysteine-containing proteins. The group of selenoproteins is represented by more than 50 protein families; however, they all appear to contribute to antioxidant and redox regulation by being selenoprotein forms of thiol oxidoreductases. The human selenoproteome consists of 25 selenoproteins which are involved in protection against oxidative stress, signal transduction, and the folding, modification, and regulation of proteins. Selenoprotein expression depends on dietary Se content. Intriguingly, recent clinical trials suggest that Se over-nutrition may significantly raise the risk of type 2 diabetes development. Subsequent studies involving mouse models demonstrated that low and high Se intake are both associated with the type 2 diabetes-like phenotype; however, specific mechanisms of this phenomenon have not been investigated. Different regions of the world are characterized by significant variations in Se content in soil and the associated variation in dietary Se content. Many regions of the United States are Se-rich, and the United States population is characterized by high levels of Se in plasma and, therefore, may have increased risk of diabetes development. In addition, the use of Se-rich dietary supplements in such areas may have a negative impact on health and increase the incidence of diabetes. The goal of this project is to investigate the roles of Se and selenoproteins in redox regulation of glucose homeostasis. The central hypothesis is that Se regulates selenoprotein synthesis which, in turn, alters redox homeostasis and influences the insulin signaling pathways. Specifically, Dr. Fomenko will define the effects of Se supplementation on redox-dependent insulin signaling. This work will be guided by two specific aims: (1) identify mechanisms underlying Se-dependent type 2 diabetes development; and (2) assess the contribution of selenoproteins to H2O2 signaling and associated control of glucose homeostasis. These aims will be addressed using a combination of biochemical and cell biology studies and animal models. The proposed study fits with the mission of the Nebraska Center for the Prevention of Obesity Diseases through Dietary Molecules (NPOD) and will help identify mechanisms of Se micronutrient-associated diabetes development. NPOD support, facilities, and mentoring will allow Dr. Fomenko to advance this project toward an independent R01 award and achieve his long-term research goals in Se biology.