Iron overload is the principal cause of morbidity and mortality in anemias characterized by ineffective erythropoiesis, including ?-thalassemias. In recent years, unprecedented progress in elucidating the molecular participants in iron metabolism has provided novel potential therapeutic approaches. In particular, the hepatic hormone hepcidin has been identified as a central regulator of iron absorption and distribution. The iron loading dyserythropoietic anemias are characterized by inappropriately low hepcidin levels despite iron loading. We have shown that exogenous transferrin ameliorates anemia, reduces circulating non-transferrin bound iron, and increases hepcidin expression in ?-thalassemic mice, suggesting that transferrin is an important regulator of the cross-talk between erythropoiesis and iron metabolism. We propose to further explore mechanisms by which transferrin regulates hepcidin expression via its roles in the erythron and in the hepatocyte. Recently HFE and transferrin receptor 2 (TfR2), molecules known to participate in the hepatic regulation of hepcidin, have been found to be also functionally important in erythroid precursors. However, the effects of transferrin on erythroid HFE and TfR2 expression and signaling, and how HFE and TfR2 modulate erythropoiesis remain largely uncharacterized. Preliminary data demonstrate that exogenous transferrin (Tf) increases the relative concentration of monoferric Tf and decreases iron entry into erythroid precursors. We propose a model in which increased monoferric transferrin alters HFE, TfR1, and TfR2 mediated iron uptake and signaling, in erythroid precursors and in hepatocytes. To test this model, we propose three specific aims: 1. Compare the binding kinetics and uptake of iron from monoferric and diferric transferrin via TfR1 and TfR2 in the presence or absence of HFE. 2. Examine the effects of changes in transferrin concentration on erythroid precursors during effective and ineffective erythropoiesis. 3. Examine the effects of changes in transferrin concentration on hepatocellular hepcidin expression. Genetically modified mice and cell lines will serve as experimental systems to test the following hypotheses: HFE modulates the ability of monoferric transferrin to compete with diferric transferrin for binding to transferrin receptors (Aim 1). Tf binding affects erythroid differentiaton through modulation of HFE, TfR1, and TfR2 expression and signaling (Aim 2A). Tf regulates erythropoiesis via TfR1/HFE-mediated changes in erythroid cellular iron status and mouse ferrokinetics (Aim 2B). Monoferric-Tf modulates hepcidin expression in hepatocytes via signaling through TfR2 (Aim 3A). Increased Tf mitigates the effects of non-transferrin bound iron on hepcidin expression (Aim 3B). Administration of Tf attenuates a hepcidin down-regulatory factor in serum of mice with dyserythropoiesis (Aim 3C). These studies will clarify the physiology of the cross-talk between iron metabolism and erythropoiesis, and potentially provide the basis for the development of novel therapeutic alternatives for patients with diseases of concurrent anemia and iron overload.
Iron overload disorders are common worldwide and can lead to severe heart and liver damage. They include certain iron loading anemias (for example, thalassemias, sickle cell anemia, and myelodysplastic syndrome) or inherited disorders of iron metabolism (hemochromatosis). We discovered that administering transferrin is an effective way of treating thalassemia in mice, and will investigate its mode of action and possible application to other forms of iron overload as well.
| Guerra, Amaliris; Musallam, Khaled M; Taher, Ali T et al. (2018) Emerging Therapies. Hematol Oncol Clin North Am 32:343-352 |
| Aschemeyer, Sharraya; Qiao, Bo; Stefanova, Deborah et al. (2018) Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin. Blood 131:899-910 |
| Oikonomidou, Paraskevi Rea; Rivella, Stefano (2018) What can we learn from ineffective erythropoiesis in thalassemia? Blood Rev 32:130-143 |
| Casu, Carla; Nemeth, Elizabeta; Rivella, Stefano (2018) Hepcidin agonists as therapeutic tools. Blood 131:1790-1794 |
| Gupta, Ritama; Musallam, Khaled M; Taher, Ali T et al. (2018) Ineffective Erythropoiesis: Anemia and Iron Overload. Hematol Oncol Clin North Am 32:213-221 |
| Casu, Carla; Presti, Vania Lo; Oikonomidou, Paraskevi Rea et al. (2018) Short-term administration of JAK2 inhibitors reduces splenomegaly in mouse models of ?-thalassemia intermedia and major. Haematologica 103:e46-e49 |
| Hotz, Meghan J; Qing, Danielle; Shashaty, Michael G S et al. (2018) Red Blood Cells Homeostatically Bind Mitochondrial DNA through TLR9 to Maintain Quiescence and to Prevent Lung Injury. Am J Respir Crit Care Med 197:470-480 |
| Nowak, Roberta B; Papoin, Julien; Gokhin, David S et al. (2017) Tropomodulin 1 controls erythroblast enucleation via regulation of F-actin in the enucleosome. Blood 130:1144-1155 |
| Muckenthaler, Martina U; Rivella, Stefano; Hentze, Matthias W et al. (2017) A Red Carpet for Iron Metabolism. Cell 168:344-361 |
| Crielaard, Bart J; Lammers, Twan; Rivella, Stefano (2017) Targeting iron metabolism in drug discovery and delivery. Nat Rev Drug Discov 16:400-423 |
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