The role of hepcidin in beta-thalassemia

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DESCRIPTION (provided by applicant): Beta-thalassemia is a monogenic disorder which occurs as a result of mutations in the beta-globin gene and is characterized by an extremely complex phenotype. Reduction of expression of the human beta-globin gene leads to ineffective erythropoiesis, splenomegaly, endocrine and bone abnormalities and interferes with iron metabolism. In addition, low levels of hemoglobin require chronic blood transfusions and iron chelation therapy to sustain life. Despite the fact that beta-thalassemia is one of the most ancient and widespread human diseases, no advances have been made in understanding the cellular processes responsible for phenotypic abnormalities and, by consequence, to new therapies. One of the main obstacles has been the lack of animal models which reproduce the beta-thalassemia phenotype. For this reason we generated the first mouse model of adult beta-thalassemia major or Cooley's anemia. These mice die of a profound anemia resulting from ineffective erythropoiesis while showing massive iron overload. The development of this novel mouse model is now contributing to the identification of key genes involved in the pathophysiology of beta-thalassemia. For instance, in a preliminary study to better understand the abnormal iron accumulation in these animals, we have investigated the expression of several genes involved in iron metabolism such as for hepcidin, an anti-microbial peptide expressed in the liver has been shown to play a role in conditions associated with both iron overload and iron deficiency. We observed hepcidin mRNA levels are decreased in the liver of mice affected by beta-thalassemia major. Our hypotheses are (1) hepcidin plays a major role in increased iron absorption in beta- thalassemia and (2) administration of hepcidin will prevent or reduce abnormal iron metabolism. (Aim 1) To study the expression of iron related genes and iron content in various tissues of normal and thalassemic mice. We will focus on the liver, spleen, kidney, heart and duodenum of both transfused and non-transfused animals. (Aim 2) To study iron levels in normal and beta-thalassemic mice in which the hepcidin gene can be constitutively expressed in liver tissue specific or housekeeping fashion. (Aim 3) To inject hepcidin into normal and beta-thalassemic mice to study its effect on iron overload. In conclusion, we believe that studying the role of hepcidin under normal and pathological conditions can contribute to the development of new prognostic tools and new pharmacological approaches to the treatment of iron overload in beta-thalassemia and related disorders.