Selenoproteins and Selenium-dependent Redox Signaling Alter Diabetes Risk

硒蛋白和硒依赖性氧化还原信号改变糖尿病风险

• 批准号: 8662975
• 负责人: Dmitri Fomenko
• 金额: $ 22.65万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 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/8662975
• 关键词: Address; Adverse effects; Animal Model; Antioxidants; Area; Award; Biochemical; Biological Process; Biology; Cell Line; Cells; Cellular biology; Chemopreventive Agent; Clinical Trials; Conflict (Psychology); Country; Data; Development; Diabetes Mellitus; Diet; Dietary Component; Dietary Selenium; Disease; Glucose; Goals; Health; Health Benefit; Homeostasis; Housekeeping; Human; Hydrogen Peroxide; Hyperinsulinism; Incidence; Individual; Insulin; Insulin Receptor; Insulin Signaling Pathway; Intake; Knockout Mice; Laboratories; Link; Mammals; Mediating; Mediator of activation protein; Mentors; Methods; Micronutrients; Mission; Modification; Molecular; Nebraska; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Overdose; Oxidation-Reduction; Oxidative Stress; Oxidoreductase; PTEN gene; PTPN1 gene; Peroxidases; Phenotype; Phosphoric Monoester Hydrolases; Plants; Plasma; Play; Population; Production; Protein Family; Protein Tyrosine Phosphatase; Proteins; Publications; Regulation; Reporting; Reproduction; Research; Risk; Role; Selenium; Selenocysteine; Signal Pathway; Signal Transduction; Signaling Molecule; Soil; Source; Study models; Sulfhydryl Compounds; Supplementation; System; Transgenic Mice; United States; Variant; Work; Yeasts; base; biological adaptation to stress; blood glucose regulation; cancer prevention; diabetes risk; dietary supplements; experience; glutathione peroxidase; immune function; insight; insulin sensitivity; insulin signaling; male; mouse model; novel; nutrition; obesity prevention; oxidation; research study; selenium deficiency; selenoprotein

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.

硒（Se）是哺乳动物必需的微量营养素，它在哺乳动物体内发挥作用， 含硒半胱氨酸的蛋白质。硒蛋白组由50多种蛋白质代表 家族;然而，它们似乎都有助于抗氧化剂和氧化还原调节硒蛋白 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， 参与抗氧化应激保护、信号转导以及蛋白质的折叠、修饰和 调节蛋白质。硒蛋白的表达依赖于膳食硒含量。有趣的是，最近 临床试验表明，硒营养过剩可能会显着增加患2型糖尿病的风险 发展随后涉及小鼠模型的研究表明，低硒和高硒摄入量 两者都与2型糖尿病样表型相关;然而，这一点的具体机制 这种现象还没有被调查过。世界不同地区的特点是， 土壤中硒含量的变化以及膳食中硒含量的相关变化。许多地区 美国是硒丰富，美国人口的特点是高水平的硒， 血浆，因此可能增加糖尿病发展的风险。此外，利用富硒 这些地区的膳食补充剂可能对健康产生负面影响，并增加 糖尿病本课题的目的是研究硒和硒蛋白在氧化还原调节中的作用 葡萄糖稳态的关键中心假设是硒调节硒蛋白的合成， 转，改变氧化还原稳态和影响胰岛素信号通路。具体来说，弗门科博士 将定义硒补充对氧化还原依赖性胰岛素信号传导的影响。这项工作将 有两个具体目标：（1）确定硒依赖型2型糖尿病的机制 开发;（2）评估硒蛋白对H2 O2信号传导和相关控制的贡献 葡萄糖稳态的关键这些目标将通过生物化学和细胞化学的结合来实现。 生物学研究和动物模型。这项拟议中的研究符合内布拉斯加州中心的使命， 通过膳食分子预防肥胖疾病（NPOD），并将有助于确定机制 硒微量营养素相关的糖尿病发展。NPOD支持、设施和指导将允许 博士Fomenko将该项目推向独立的R 01奖项，并实现他的长期目标。 硒生物学的研究目标。