Roles of Neogenin and Matriptase-2 in Hemojuvelin-Mediated Hepcidin Expression

 描述（由申请方提供）：该提案针对铁过载疾病和铁限制性贫血的分子基础，这是全球最常见的血液病之一。铁稳态或其紊乱的分子机制还不清楚。最近的研究已经确定铁调节激素铁调素作为负责调节全身铁稳态的关键分子。铁调素主要在肝细胞中表达，其表达受身体铁负荷的正调控。Hemojuvelin（HJV）和matriptase-2（MT 2）是铁调素表达的一对关键调节因子。HJV是一个强大的诱导剂，而MT 2是一个重要的抑制剂，通过切割HJV成无活性的形式。人类中功能性HJV的缺乏显著降低铁调素表达并引起青少年血色病，这是铁过载疾病的最严重形式。MT 2的突变不适当地增加铁调素表达并导致铁难治性缺铁性贫血。HJV和MT 2都在肝细胞中表达，并与再生蛋白（一种普遍表达的蛋白质）相互作用。在转染细胞中的研究强烈表明，再生蛋白是HJV和MT 2的功能所必需的。然而，再生蛋白在铁稳态中的作用尚不清楚。更重要的是，肝细胞的铁敏感机制尚不清楚，它仍然是铁代谢领域的一个关键问题。长期目标是更好地了解系统性铁稳态的机制。该特定应用的目的是表征再生蛋白、HJV和MT 2在铁调素表达调节中的协调。我们的中心假设是，再生蛋白和HJV构成了一个轴，以设定肝细胞中铁调素表达的基础水平，身体铁负荷负调控MT 2和肝细胞硫酸乙酰肝素蛋白聚糖（HSPG）的脱落，间接调节铁调素表达到适当的水平。这一假设是根据申请人和其他实验室提供的数据提出的。这项研究的基本原理是，了解铁对铁调素表达的调节有可能为铁超载疾病和铁限制性贫血开发新的治疗方法。在强有力的初步数据的指导下，将通过追求两个具体目标来测试该假设：1）确定肝细胞再生蛋白在铁调素表达中的重要作用; 2）确定MT 2的铁调节是否作为关键铁传感器来调节铁调素表达的诱导。该方法是创新的，因为它专注于再生蛋白，HJV，MT 2和HSPG在铁调节铁调素表达的分子，细胞和系统水平上的机制研究。这项研究意义重大，因为它有望为药理学策略的发展提供基础。这些研究的成功完成不仅将增加我们对全身铁稳态机制的理解，而且还为将这些进展转化为铁障碍患者的切实利益奠定了基础。

 DESCRIPTION (provided by applicant): This proposal targets the molecular basis of iron overload disorders and iron-restricted anemias, which are among the most common hematological diseases worldwide. The molecular mechanisms of iron homeostasis or its disorders are not well understood. Recent studies have identified the iron-regulatory hormone hepcidin as the key molecule responsible for the regulation of systemic iron homeostasis. Hepcidin is expressed predominantly in hepatocytes, and its expression is positively regulated by bodily iron load. Hemojuvelin (HJV) and matriptase-2 (MT2) are a pair of pivotal regulators for hepcidin expression. HJV is a robust inducer, whereas MT2 is an essential suppressor by cleaving HJV into inactive forms. Lack of functional HJV in humans markedly decreases hepcidin expression and causes juvenile hemochromatosis, the most severe form of iron overload disorders. Mutations of MT2 inappropriately increase hepcidin expression and lead to iron-refractory iron-deficiency anemia. Both HJV and MT2 are expressed in hepatocytes, and interact with neogenin, a ubiquitously expressed protein. Studies in transfected cells strongly indicate that neogenin is required for the function of HJV and MT2. However, the role of neogenin in iron homeostasis is not known. More importantly, the iron-sensing mechanism in hepatocytes is poorly understood, and it remains to be a key issue in the field of iron metabolism. The long-term goal is to better understand the mechanism of systemic iron homeostasis. The objective of this particular application is to characterize the coordination of neogenin, HJV, and MT2 in the regulation of hepcidin expression. Our central hypothesis is that neogenin and HJV constitute an axis to set the basal level of hepcidin expression in hepatocytes, and that bodily iron load negatively regulates MT2 and the shedding of hepatocyte heparan sulfate proteoglycans (HSPG) to indirectly adjust hepcidin expression to an appropriate level. This hypothesis has been formulated on the basis of the data produced by the applicants' and other laboratories. The rationale for the proposed research is that understanding the regulation of hepcidin expression by iron has the potential to develop new therapies for iron overload disorders and iron-restricted anemias. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Determine the essential role of hepatocyte neogenin in hepcidin expression; 2) determine whether iron regulation of MT2 acts as a key iron sensor to modulate the induction of hepcidin expression. The approach is innovative, because it focuses on the mechanistic studies of neogenin, HJV, MT2, and HSPG in iron-regulated hepcidin expression at molecular, cellular and systemic levels. The proposed research is significant, because it is expected to provide the basis for the development of pharmacologic strategies. Successful completion of these studies will not only increase our understanding of systemic iron homeostatic mechanism but also lay the foundation for translating these advances into tangible benefits for patients with iron disorders.