The role of hepcidin in beta-thalassemia

描述（由申请人提供）：β -地中海贫血是一种单基因疾病，由β -珠蛋白基因突变引起，其特征是极其复杂的表型。人β -珠蛋白基因表达减少导致红细胞生成功能低下、脾肿大、内分泌和骨异常，并干扰铁代谢。此外，血红蛋白水平低需要长期输血和铁螯合治疗来维持生命。尽管β -地中海贫血是最古老、最普遍的人类疾病之一，但在理解导致表型异常的细胞过程以及由此产生的新疗法方面没有取得任何进展。主要障碍之一是缺乏重现-地中海贫血表型的动物模型。因此，我们建立了第一个成年-地中海贫血或库利贫血的小鼠模型。这些小鼠死于严重的贫血，这是由于红细胞生成无效而导致的，同时显示出大量的铁过载。这种新型小鼠模型的发展现在有助于鉴定参与-地中海贫血病理生理的关键基因。例如，在一项初步研究中，为了更好地了解这些动物体内的异常铁积累，我们研究了几个与铁代谢有关的基因的表达，如hepcidin，肝脏中表达的一种抗微生物肽，已被证明在铁过载和铁缺乏相关的条件下发挥作用。我们观察到-地中海贫血小鼠肝脏中hepcidin mRNA水平降低。我们的假设是：(1)hepcidin在β -地中海贫血中增加铁吸收中起主要作用；(2)给予hepcidin可以预防或减少铁代谢异常。（目的1）研究正常小鼠和地中海贫血小鼠各组织中铁相关基因的表达及铁含量。我们将重点关注输血和非输血动物的肝脏、脾脏、肾脏、心脏和十二指肠。（目的2）研究正常和β -地中海贫血小鼠的铁水平，其中hepcidin基因可以在肝组织特异性或内务方式中组成性表达。（目的3）将hepcidin注射到正常和地中海贫血小鼠体内，研究其对铁超载的影响。总之，我们相信研究hepcidin在正常和病理条件下的作用有助于开发新的预后工具和新的药物方法来治疗-地中海贫血和相关疾病的铁超载。

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.