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疾病中血红蛋白合成和红细胞生成的调节。在本研究中，我们重点研究了血红素调节的eIF 21激酶（HRI）信号通路在慢性缺铁和缺铁性贫血的氧化应激和应激红细胞生成中的作用。地中海贫血我们的实验室已经证明，HRI是必要的，以减少无效的红细胞生成，并保持适当的基因表达在红细胞前体在缺铁期间，除了珠蛋白合成的翻译控制。HRI对于降低？-地中海贫血最近，我们发现了一个新的作用，HRI在红细胞分化在缺铁性贫血和2-地中海贫血。此外，HRI还诱导类红细胞谱系中氧化应激时的ATF 4应激反应途径，以减轻活性氧（ROS）和细胞凋亡的水平。我们假设HRI介导的eIF 21 P-ATF 4应激反应途径是必要的，以减少氧化应激和促进红细胞分化在应激红细胞生成。我们将研究这一假设使用体内应力模型？-地中海贫血和缺铁性贫血。将使用eIF 21磷酸化的红细胞特异性消融和ATF 4-/-小鼠模型描绘信号传导途径。无效红细胞生成发生在？-地中海贫血是这种疾病和其他红细胞疾病与血红蛋白病的主要并发症的来源。从我们提出的研究结果应进一步推进我们的理解无效的红细胞生成的分子机制和HRI的红系细胞的生长和分化的功能，在压力条件下，在疾病状态。这项研究的结果也可能导致HRI及其信号通路在治疗地中海贫血和其他红细胞疾病中的潜在应用。贫血在慢性炎症、癌症和糖尿病患者中以及在衰老时也很普遍。这些拟议研究的结果也可能为这些贫血提供见解。 公共卫生相关性：这项研究的目的是进一步了解缺铁性贫血和缺铁性贫血患者红细胞发育无效的分子机制。地中海贫血这项研究的结果可能会导致发现新的药物治疗红细胞疾病。

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.