HRI-eIF2a Phosphorylation Signaling in Oxidative Stress and Erythropoiesis

描述(由申请人提供)：我们这项拟议研究的长期目标是有助于更全面地了解应激条件下和红细胞紊乱情况下的血红蛋白合成和红细胞生成的调节。在这项研究中，我们着重于血红素调节的eIF21激酶(HRI)信号通路在慢性缺铁性贫血和地中海贫血的氧化应激和应激性红细胞生成中的作用。我们的实验室已经证明，除了对珠蛋白合成的翻译控制外，在缺铁期间，HRI对于减少无效的红细胞生成和维持红系前体细胞适当的基因表达是必要的。HRI对于降低β-地中海贫血的表型严重性也是必不可少的。最近，我们发现了HRI在缺铁性贫血和2-地中海贫血的红系分化中的新作用。此外，HRI还在红系细胞中诱导氧化应激下的ATF4应激反应途径，以减轻活性氧(ROS)水平和细胞凋亡。我们推测，HRI介导的eIF21P-ATF4应激反应通路在应激性红细胞生成过程中对于减少氧化应激和促进红系分化是必要的。我们将使用β-地中海贫血和缺铁性贫血的体内应激模型来研究这一假说。信号通路将通过红系特异性去除eIF21磷酸化和ATF4-/-小鼠模型来描绘。β-地中海贫血中出现的无效的红细胞生成是这种疾病和其他伴有血红蛋白病的红细胞疾病的主要并发症的来源。我们的研究结果将进一步促进我们对无效红细胞生成的分子机制的理解，以及HRI在应激条件下和疾病状态下红系细胞生长和分化中的作用。这项拟议的研究结果也可能导致HRI及其信号通路在治疗地中海贫血和其他红细胞疾病方面的潜在应用。贫血在慢性炎症、癌症和糖尿病患者中也很普遍，随着年龄的增长也是如此。这些拟议研究的结果也可能为这些贫血提供洞察力。 公共卫生相关性：这项拟议研究的目的是进一步了解缺铁性贫血和地中海贫血患者红细胞发育无效的分子机制。这项研究的结果可能会导致发现治疗红细胞疾病的新药物。

DESCRIPTION (provided by applicant): Our long-term objective of this proposed research is to contribute to the more comprehensive understanding of the regulation of hemoglobin synthesis and erythropoiesis under stress conditions and in red cell disorders. In this proposal, we focus on the role of the heme-regulated eIF21 kinase (HRI) signaling pathway in oxidative stress and stress erythropoiesis of chronic iron deficiency and ?-thalassemia. Our laboratory has demonstrated that HRI is necessary to reduce ineffective erythropoiesis and to maintain proper gene expression in erythroid precursors during iron deficiency, in addition to translational control of globin synthesis. HRI is also essential for reducing the phenotypic severities of ?-thalassemia. Recently, we uncovered a novel role of HRI in erythroid differentiation during iron deficiency anemia and in 2-thalassemia. Additionally, HRI also induces the ATF4 stress response pathway upon oxidative stress in the erythroid lineage to mitigate levels of reactive oxygen species (ROS) and apoptosis. We hypothesize that the HRI mediated eIF21P-ATF4 stress response pathway is necessary to reduce oxidative stress and to promote erythroid differentiation during stress erythropoiesis. We will investigate this hypothesis using in vivo stress models of ?- thalassemia and iron deficiency anemia. The signaling pathway will be delineated using erythroid specific ablation of eIF21 phosphorylation and ATF4-/- mouse models. Ineffective erythropoiesis that occurs in ?- thalassemia is the source of major complications in this disease and other red cell disorders with hemoglobinopathy. Results from our proposed studies should further advance our understanding of the molecular mechanism of ineffective erythropoiesis and the functions of HRI in the growth and differentiation of erythroid cells under stress conditions and in disease states. The outcome of this proposed study might also lead to potential application of HRI and its signaling pathway in treating thalassemia and other red cell diseases. Anemia is also prevalent in patients with chronic inflammations, cancers, and diabetes as well as upon aging. The outcome of these proposed studies might also provide insights into these anemias. PUBLIC HEALTH RELEVANCE: The purpose of this proposed research is to further our understanding of the molecular mechanisms of ineffective red blood cell development in anemias of iron deficiency and ?-thalassemia. The outcome of this study may lead to the discovery of novel drug treatment for red blood cell diseases.