Selenium, Selenoproteins, and Stress Erythropoiesis

硒、硒蛋白和应激性红细胞生成

基本信息

批准号：
10096670
负责人：
ROBERT Frank PAULSON
金额：
$ 15.8万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10096670
关键词：
3&apos Untranslated Regions Acute Affect Affinity Anemia Anti-Inflammatory Agents Antioxidants BFU-E Binding Bone Marrow Bone Marrow Transplantation CRISPR/Cas technology Cytoplasm DNA Insertion Elements Data Defect Development Dietary Selenium Dinoprostone Elderly Erythroblasts Erythrocytes Erythroid Erythropoiesis Foundations Free Radicals Gatekeeping Genetic Transcription Globin Heme Hemolysis Homeostasis Human Impairment In Vitro Inflammatory Iron Island Knock-out Lead Mediating Messenger RNA Methods Modeling Mus Muscle satellite cell Mutation Output Oxidation-Reduction Oxidative Stress Pathway interactions Patients Phosphotransferases Play Population Process Production Proliferating Proteins Reactive Oxygen Species Recovery Regulation Risk Role SelW protein Selenium Selenocysteine Serum Sickle Cell Anemia Signal Transduction Spleen Splenic Red Pulp Stress Structure Terminator Codon Testing Transfer RNA Work anti-cancer base erythroid differentiation glutathione peroxidase in vivo lipid mediator macrophage migration monocyte novel oxidative damage polypeptide progenitor programs recruit response selenium deficiency selenoprotein stem cells therapy design transcription factor transplant model

项目摘要

Selenium (Se) functions as a redox gatekeeper through its incorporation as selenocysteine (Sec) in selenoproteins. This co-translational process is highly regulated by Sec insertion sequence (SECIS) in the 3’ UTR of mRNA, which allows the tRNA[Sec] (encoded by Trsp), to recognize a UGA stop codon and insert Sec into the growing polypeptide chain. Erythropoiesis presents a particular problem to redox regulation as the presence of iron, heme, and unpaired globin chains can lead to high levels of free radical-mediated oxidative stress, which are detrimental to erythroid development and can lead to anemia. Under homeostatic conditions, bone marrow erythropoiesis produces sufficient erythrocytes to maintain homeostasis. In contrast, anemic stress induces an alternative pathway, stress erythropoiesis, which rapidly produces new erythrocytes to alleviate the anemia. In line with their antioxidant, anticancer, and anti-inflammatory functions, selenoproteins protect erythrocytes from oxidative damage, while their absence causes hemolysis of erythrocytes due to oxidative stress. We have recently demonstrated that Se deficiency or lack of selenoproteins severely impaired stress erythropoiesis exacerbating anemia. These data support observations in patients where low serum Se is associated with increased risk of anemia in the elderly. Similarly, sickle cell anemia (SCA) patients present with significantly lower serum Se and glutathione peroxidase (GPX) activity suggesting that impaired erythrocyte stability and defective erythropoietic response may in part result from a decreased antioxidant potential to effectively metabolize pro-oxidant species. Macrophages play a key role in erythropoiesis. Erythroid progenitors develop in close proximity with macrophages in structures referred to as erythroblastic islands (EBIs). Se deficiency or lack of selenoproteins impairs the development of EBIs in the splenic niche and compromises the recovery from anemia. These data suggest that selenoproteins are critical in both the progenitors and the microenvironment to regulate stress erythropoiesis. The proposed studies are based on the hypothesis that Se, through selenoproteins, plays a key role in supporting effective stress erythropoiesis and erythroid development to enable recovery from anemia by affecting both stress erythroid progenitors (SEPs) and the erythropoietic niche that contains macrophages. The hypothesis will be tested using a bone marrow transplant model of anemia along with other secondary acute anemia models in the following specific aims: 1) Examine the role of SelenoW in erythroid differentiation during acute anemia; 2) Dissect the role of selenoproteins in monocytes/macrophages in the establishment of EBIs during stress erythropoiesis; 3) Examine the role of selenoproteins in the regulation of the proliferation and differentiation of SEPs. Successful completion of this proposal will increase our understanding of how selenoproteins regulate stress erythropoiesis and establish a foundation for the development of new treatments designed to increase erythroid output by manipulating the redox gatekeepers in progenitor cells as well as the stress erythropoietic niche.

硒 (Se) 通过与硒代半胱氨酸 (Sec) 结合而发挥氧化还原看门人的作用这种共翻译过程受到 3' 中的 Sec 插入序列 (SECIS) 的高度调控。 mRNA 的 UTR，允许 tRNA[Sec]（由 Trsp 编码）识别 UGA 终止密码子并插入 Sec 进入生长的多肽链中，红细胞生成对氧化还原调节提出了一个特殊的问题。铁、血红素和不配对的珠蛋白链的存在可导致高水平的自由基介导的氧化压力会影响红细胞发育并在稳态条件下导致贫血。骨髓红细胞生成产生足够的红细胞以维持体内平衡，相反，贫血应激。诱导另一种途径，应激性红细胞生成，快速产生新的红细胞以缓解硒蛋白具有抗氧化、抗癌和抗炎功能，可保护贫血。红细胞免受氧化损伤，而它们的缺失会导致红细胞因氧化而溶血我们最近证明，硒缺乏或缺乏硒蛋白会严重损害压力。红细胞生成加剧贫血。这些数据支持低血清硒患者的观察结果。同样，镰状细胞性贫血（SCA）患者也与老年人贫血风险增加相关。血清硒和谷胱甘肽过氧化物酶（GPX）活性显着降低，表明红细胞受损稳定性和红细胞生成反应缺陷可能部分是由于抗氧化潜力降低造成的红细胞祖细胞有效地代谢促氧化物质，在红细胞生成中发挥关键作用。在称为成红细胞岛 (EBI) 的结构中与巨噬细胞紧密结合。硒蛋白的缺乏或缺乏会损害脾微环境中 EBI 的发育并损害这些数据表明，硒蛋白对于祖细胞和细胞都至关重要。调节应激性红细胞生成的微环境所提出的研究基于以下假设：硒通过硒蛋白在支持有效应激红细胞生成和红细胞生成方面发挥着关键作用通过影响应激性红细胞祖细胞（SEP）和含有巨噬细胞的红细胞生成生态位将使用骨髓进行测试。贫血移植模型以及其他继发性急性贫血模型，其具体目标如下：1) 检查 SelenoW 在急性贫血期间红细胞分化中的作用；2) 剖析 3）检查硒蛋白在 SEP 增殖和分化调节中的作用成功完成。该提案将增加我们对硒蛋白如何调节应激性红细胞生成和为开发旨在增加红细胞输出的新疗法奠定基础操纵祖细胞中的氧化还原看门人和应激性红细胞生成生态位。