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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Erythrocyte and Leukocyte Biology Study Section (ELB)
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Bishop, Terry Rogers
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Massachusetts Institute of Technology
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United States
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Zhang, Shuping; Macias-Garcia, Alejandra; Velazquez, Jason et al. (2018) HRI coordinates translation by eIF2?P and mTORC1 to mitigate ineffective erythropoiesis in mice during iron deficiency. Blood 131:450-461
Yang, Xi; Xia, Rui; Yue, Cuihua et al. (2018) ATF4 Regulates CD4+ T Cell Immune Responses through Metabolic Reprogramming. Cell Rep 23:1754-1766
Chen, Jane-Jane (2014) Stress-enhanced translation of ?-globin mRNA. Blood 124:2622-3
Chen, Jane-Jane (2014) Translational control by heme-regulated eIF2? kinase during erythropoiesis. Curr Opin Hematol 21:172-8
Chen, Jane-Jane; Perrine, Susan (2013) Stressing HbF synthesis: role of translation? Blood 122:467-8
Suragani, Rajasekhar N V S; Zachariah, Roshini S; Velazquez, Jason G et al. (2012) Heme-regulated eIF2? kinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis. Blood 119:5276-84
Acharya, Poulomi; Chen, Jane-Jane; Correia, Maria Almira (2010) Hepatic heme-regulated inhibitor (HRI) eukaryotic initiation factor 2alpha kinase: a protagonist of heme-mediated translational control of CYP2B enzymes and a modulator of basal endoplasmic reticulum stress tone. Mol Pharmacol 77:575-92