The role of hepcidin in beta-thalassemia

描述(申请人提供)：β-地中海贫血是一种单基因疾病，它是由于β-珠蛋白基因突变而发生的，具有极其复杂的表型特征。人类β-珠蛋白基因的表达减少会导致红细胞生成无效、脾肿大、内分泌和骨骼异常，并干扰铁的代谢。此外，低水平的血红蛋白需要长期输血和铁络合疗法来维持生命。尽管β-地中海贫血是人类最古老和最普遍的疾病之一，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复制β-地中海贫血表型的动物模型。出于这个原因，我们建立了第一个成年重型β地中海贫血或库利氏贫血的小鼠模型。这些小鼠死于一种严重的贫血，这是由于无效的红细胞生成造成的，同时表现出大量的铁超载。这一新的小鼠模型的发展现在有助于识别与β-地中海贫血病理生理学有关的关键基因。例如，在一项初步研究中，为了更好地了解这些动物中的异常铁积累，我们调查了几个与铁代谢有关的基因的表达，例如在肝脏中表达的抗菌肽海普西丁，已被证明在与铁超载和缺铁相关的条件下发挥作用。我们观察到，受严重β-地中海贫血影响的小鼠肝脏中海普西丁的mRNA水平降低。我们的假设是：(1)海普西丁在增加β-地中海贫血患者的铁吸收中起主要作用；(2)给予海普西丁可预防或减少异常的铁代谢。(目的1)研究正常和地中海贫血小鼠不同组织中铁相关基因的表达和铁含量。我们将重点研究输血和未输血动物的肝、脾、肾、心脏和十二指肠。(目的2)研究正常小鼠和β-地中海贫血小鼠的铁水平，在这些小鼠中，海普西丁基因可以以肝组织特异性或管家的方式结构性表达。(目的3)给正常和β-地中海贫血小鼠注射海普西丁，研究其对铁超载的影响。总之，我们相信，研究海普西丁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理学方法来治疗β-地中海贫血和相关疾病的铁负荷。

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.