Methods and compositions to regulate iron metabolism
The present invention provides new systems and strategies for the regulation of iron metabolism in mammals. In particular, methods of using agonists and antagonists of TGF-β superfamily members to modulate the expression or activity of hepcidin, a key regulator of iron metabolism, are described. The inventive methods find applications in the treatment of diseases associated with iron overload, such as juvenile hemochromatosis and adult hemochromatosis, and in the treatment of diseases associated with iron deficiency, such as anemia of chronic disease and EPO resistant anemia in end-stage of renal disease. The present invention also relates to screening tools and methods for the development of novel drugs and therapies for treating iron metabolism disorders.
1. A fusion protein comprising:
(a) an extracellular domain or soluble portion of human hemojuvelin (HJV), wherein HJV comprises the amino acid sequence of SEQ ID NO:24, and wherein said domain or portion comprises an alanine, an aspartic acid or a deletion at the position corresponding to residue 172 of SEQ ID NO:24; and
(b) Fc
wherein said fusion protein increases bone morphogenic protein signal in vitro.
2. The fusion protein of claim 1 , wherein said Fc is human Fc.
3. A pharmaceutical composition comprising the fusion protein of claim 1 and a pharmaceutically acceptable carrier.
4. The method fusion protein of claim 1 , wherein said extracellular domain or soluble portion of HJV lacks an N-terminal signal sequence.
5. The fusion protein of claim 1 , wherein the extracellular domain or soluble portion of HJV comprises amino acids 1-400 of SEQ ID NO:24.
6. The fusion protein of claim 4 , wherein the extracellular domain or soluble portion of HJV comprises amino acids 35-400 of SEQ ID NO:24.