Selenium, Selenoproteins, and Stress Erythropoiesis

硒、硒蛋白和应激性红细胞生成

• 批准号: 10197916
• 负责人: ROBERT Frank PAULSON
• 金额: $ 30.53万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197916
• 关键词: 3' 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

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）通过与硒半胱氨酸（Sec）结合而起氧化还原守门人的作用