Selenium, Selenoproteins, and Stress Erythropoiesis

硒(Se)以硒半胱氨酸(Sec)的形式掺入体内，起到氧化还原把关的作用 硒蛋白。这种共翻译过程受3‘端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 进入不断增长的多肽链。红细胞生成对氧化还原调节提出了一个特别的问题，因为 铁、血红素和未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，这是有害的红系发育，并可能导致贫血。在动态平衡条件下， 骨髓红血球生成足够的红血球来维持体内平衡。相比之下，贫血压力 诱导另一种途径，应激性红细胞生成，迅速产生新的红细胞来缓解 贫血。与其抗氧化、抗癌和抗炎功能一致，硒蛋白可以保护 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 压力。我们最近已经证明，缺硒或缺硒蛋白会严重损害压力。 红血球生成加剧贫血。这些数据支持低血清硒水平患者的观察。 与老年人贫血风险增加有关。同样，镰状细胞性贫血(SCA)患者患有 显著降低血清Se和谷胱甘肽过氧化物酶(GPX)活性，表明红细胞受损 稳定性和有缺陷的红细胞生成反应可能部分是由于抗氧化潜力降低所致 有效代谢抗氧化剂物种。巨噬细胞在红细胞生成中起着关键作用。红系祖细胞 在接近巨噬细胞的结构中发育，称为红细胞岛(EBI)。硒 硒蛋白缺乏或缺乏会损害脾脏壁龛内EBI的发育，并损害 从贫血中恢复过来。这些数据表明，硒蛋白在祖细胞和 调节应激性红细胞生成的微环境。拟议的研究是基于这样一个假设： 硒通过硒蛋白在支持有效应激性红细胞生成和红系生成中起关键作用。 通过影响应激红系祖细胞(SEP)和 含有巨噬细胞的红血球细胞的壁龛。这一假说将通过骨髓进行检验。 移植贫血模型与其他继发性急性贫血模型的具体目的如下：1) 研究SelenoW在急性贫血时红系分化中的作用；2)剖析 单核/巨噬细胞中的硒蛋白在应激性红细胞生成过程中EBI的建立；3)检查 硒蛋白在SEPs增殖和分化调控中的作用。成功完成 这一建议将增加我们对硒蛋白如何调节应激性红细胞生成和 为开发旨在通过以下方式增加红系产量的新疗法奠定基础 操纵祖细胞中的氧化还原守门人以及应激红系细胞的生态位。

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.