EXCEED THE SPACE PROVIDED. Our long-term objective is to contribute to the understanding of the regulation of hemoglobin synthesis and erythroid differentiation in normal and abnormal hematological conditions, with particular emphasis on the roles of heme and protein synthesis in these processes. Protein synthesis in intact reticulocytes and their lysates is dependent on the availability of heme. Heme serves as the prosthetic group of the hemoglobin, the predominant protein in red blood cell (RBC) and its late precursor cells. Biochemical studies have shown that, under conditions of heine-deficiency or iron-deficiency, protein synthesis is inhibited at the level of initiation due to the activation of the heme-regulated translational inhibitor (HRI). HRI is a heme-regulated protein kinasc that phosphorylates the ct-subunit of eukaryotic initiation factor 2 (eIF2a). Phosphorylation of the ct-subunit of eIF2 impairs its recycling in translational initiation and results in the cessation of protein synthesis. The research designs are (1) To Elucidate the Molecular Mechanism by which HRI Regulates Red Blood Cell Production, (2) To Assess the Protective Role of HRI in Red Blood Cell Disorders, and (3) To Delineate the Molecular Mechanism of Stress-Activation of HRI. The methods to be employed are the generation of genetically modified mice, hematological analysis, histological and electron microscopic examinations, colony culture assays for erythroid progenitors, Western-blot analysis and protein kinase assays, cell culture, phenotypic examination of mouse embryos, recombinant DNA techniques. Our recent study indicate that HRI is not only necessary for globin synthesis, but also for heine biosynthesis. HRI is also important for the survival of mice with thalassemia and erythropoietic protoporphria. Our proposed study may lead to potential application of HRI in treating human patients with red cell diseases. PERFORMANCE SITE ========================================Section End===========================================

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hematology Subcommittee 2 (HEM)
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Bishop, Terry Rogers
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Massachusetts Institute of Technology
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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
Liu, Sijin; Suragani, Rajasekhar N V S; Wang, Fudi et al. (2007) The function of heme-regulated eIF2alpha kinase in murine iron homeostasis and macrophage maturation. J Clin Invest 117:3296-305
Chen, Jane-Jane (2007) Regulation of protein synthesis by the heme-regulated eIF2alpha kinase: relevance to anemias. Blood 109:2693-9
McEwen, Edward; Kedersha, Nancy; Song, Benbo et al. (2005) Heme-regulated inhibitor kinase-mediated phosphorylation of eukaryotic translation initiation factor 2 inhibits translation, induces stress granule formation, and mediates survival upon arsenite exposure. J Biol Chem 280:16925-33
Han, An-Ping; Fleming, Mark D; Chen, Jane-Jane (2005) Heme-regulated eIF2alpha kinase modifies the phenotypic severity of murine models of erythropoietic protoporphyria and beta-thalassemia. J Clin Invest 115:1562-70
Lu, Linrong; Chen, Jane Jane (2002) Molecular cloning and characterization of the promoter of mouse heme-regulated eIF2alpha kinase. Biochim Biophys Acta 1574:193-9
Bauer, B N; Rafie-Kolpin, M; Lu, L et al. (2001) Multiple autophosphorylation is essential for the formation of the active and stable homodimer of heme-regulated eIF2alpha kinase. Biochemistry 40:11543-51
Kumar, R; Azam, S; Sullivan, J M et al. (2001) Brain ischemia and reperfusion activates the eukaryotic initiation factor 2alpha kinase, PERK. J Neurochem 77:1418-21
Rosenwald, I B; Pechet, L; Han, A et al. (2001) Expression of translation initiation factors elF-4E and elF-2alpha and a potential physiologic role of continuous protein synthesis in human platelets. Thromb Haemost 85:142-51

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