Our long-term objectives of this proposed research are to contribute to the more comprehensive understandings of the regulation of hemoglobin synthesis and erythroid differentiation, as well as the molecular basis of the pathology of red cell disorders with hemoglobinopathy. In this proposal, we focus on the role of heme-regulated eIF2a kinase (HRI) and its signaling pathway in these processes. HRI plays an essential protective role in iron deficiency anemia, ?-thalassemia and erythropoietic protoporphyria. HRI is necessary to reduce ineffective erythropoiesis and to maintain proper gene expression in erythroid precursors during iron deficiency. Most recently, we have uncovered the novel function of HRI in macrophages, and extended the role of HRI beyond the erythroid lineage.
The specific aims for this proposal are (1) To Elucidate the Molecular Mechanisms of Ineffective Erythropoiesis in Iron Deficiency and ?- Thalassemia. (2) To Elucidate the Role of HRI in the Interaction of Macrophages and Erythroblasts. (3) To Elucidate HRI Signaling Pathway in Oxidative Stress. The methods employed are quantitative RT-PCR, western blot analysis, cell culture, lentiviral expression system, immunofluorescent microscopy, isolation and reconstitution of erythroblastic islands, knockout mice, and recombinant DNA techniques. 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 the potential application of HRI and its signaling pathway in treating thalassemia and other anemia, which is also prevalent in patients with chronic inflammations, cancers, and diabetes, as well as upon aging. Chronic exposure to arsenite in the drinking water is known to cause anemia and cancers in humans. Furthermore, arsenite has been used successfully to treat acute promyelocytic leukemia, and is under clinical trials for multiple myeloma and other solid tumors currently. The small chemicals discovered in this proposed research might also have great potential in helping to treat drug-resistant cancer cells.
| 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 |
