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）通过其作为硒代半胱氨酸（SEC）的氧化还原守门人发挥作用硒蛋白。该共同翻译过程受到3'中的SEC插入序列（SECI）的高度调节 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。红细胞生成给氧化还原调节提出了一个特殊的问题铁，血红素和未配对的球蛋白链的存在会导致高水平的自由基介导的氧化物压力，对红细胞发育有害并可能导致贫血。在稳态条件下，骨髓红细胞生成产生足够的红细胞来维持稳态。相反，贫血压力诱导替代途径，压力红细胞生成，该途径迅速产生新的红细胞以减轻贫血。与它们的抗氧化剂，抗癌和抗炎功能一致，硒蛋白保护因氧化损伤而导致的红细胞，而它们的缺失会导致氧化引起的红细胞溶血压力。我们最近证明了SE缺乏或缺乏硒蛋白严重受损的压力促红细胞生成贫血。这些数据支持低血清SE的患者的观察结果与老年贫血风险增加有关。同样，镰状细胞贫血（SCA）患者血清SE和谷胱甘肽过氧化物酶（GPX）的显着降低，表明红细胞受损稳定性和促红细胞生成反应可能部分是由于抗氧化潜力降低而导致的有效地代谢促氧化物种。巨噬细胞在红细胞生成中起关键作用。红细胞祖细胞与巨噬细胞的结构密切相近，称为红细胞岛（EBIS）。缺乏症或缺乏硒蛋白会损害脾脏利基中的EBIS的发展，并损害从贫血中恢复。这些数据表明，硒蛋白在祖细胞和微环境调节压力红细胞生成。拟议的研究基于以下假设 SE，通过硒蛋白，在支持有效的压力红细胞生成和红细胞状态中起着关键作用通过影响压力红斑祖细胞（SEP）和含有巨噬细胞的红细胞生态位。该假设将使用骨髓进行检验在以下特定目的中，贫血的移植模型以及其他继发性急性贫血模型：1）检查硒在急性贫血期间的红细胞分化中的作用； 2）剖析在压力红细胞生成期间，单核细胞/巨噬细胞中的硒蛋白； 3）检查硒蛋白在SEP的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压力红细胞生成和的理解为开发旨在增加红细胞输出的新疗法建立基础操纵祖细胞中的氧化还原守门人以及压力促红细胞生小众。