Selenium, Selenoproteins, and Stress Erythropoiesis

硒（Se）通过其作为硒代半胱氨酸（Sec）掺入到细胞中而起到氧化还原看门人的作用。 硒蛋白该共翻译过程受到3'端的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 进入生长中的多肽链。红细胞生成对氧化还原调节提出了一个特殊的问题， 铁、血红素和未配对的球蛋白链的存在可导致高水平的自由基介导的氧化 压力，这是有害的红细胞发育，并可能导致贫血。在体内平衡的条件下， 骨髓红细胞生成产生足够的红细胞以维持体内平衡。相反，贫血压力 诱导替代途径，应激红细胞生成，迅速产生新的红细胞，以减轻 贫血硒蛋白具有抗氧化、抗癌和抗炎功能， 红细胞免受氧化损伤，而它们的缺乏会导致红细胞因氧化损伤而溶血。 应力我们最近发现硒缺乏或缺乏硒蛋白严重损害应激 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， 与老年人贫血风险增加有关。类似地，镰状细胞性贫血（SCA）患者存在以下症状： 血清硒和谷胱甘肽过氧化物酶（GPX）活性显著降低，提示红细胞受损 稳定性和有缺陷红细胞生成反应可能部分是由于抗氧化能力降低， 有效地代谢促氧化剂种类。巨噬细胞在红细胞生成中起关键作用。红系祖细胞 在称为成红细胞岛（EBI）的结构中与巨噬细胞紧密接近地发展。Se 硒蛋白的缺乏或缺乏会损害脾龛中EBI的发展， 从贫血中恢复。这些数据表明，硒蛋白在祖细胞和 微环境调节应激红细胞生成。拟议的研究是基于这样的假设， 硒通过硒蛋白在支持有效应激红细胞生成和红系细胞中起关键作用 通过影响应激红系祖细胞（SEP）和 含有巨噬细胞的红细胞生成生态位。我们将用骨髓样本来检验这个假设 贫血的移植模型沿着其他继发性急性贫血模型，具体目的如下：1） 研究硒在急性贫血红系分化中的作用; 2）分析硒在急性贫血红系分化中的作用。 单核细胞/巨噬细胞中硒蛋白在应激红细胞生成过程中EBI建立中的作用; 3）检查 硒蛋白在调控SEPs增殖和分化中的作用。成功完成 这一建议将增加我们对硒蛋白如何调节应激红细胞生成的理解， 为开发旨在增加红细胞输出的新治疗方法奠定基础， 操纵祖细胞中的氧化还原门控以及应激红细胞生成小生境。

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.