ROLES OF NEOGENIN AND MATRIPTASE-2 IN IRON HOMEOSTASIS

该提案针对铁超负荷疾病和铁限制性贫血的分子基础，这是世界上最常见的血液病之一。最近的研究已经证明铁调节激素铁调素是负责全身铁稳态的关键分子。铁调素表达通过骨形态发生蛋白信号传导途径介导，并且需要其他关键质膜蛋白的参与，包括血幼素（HJV）、血色素沉着蛋白（HFE）、转铁蛋白受体-2（TfR 2）和再生蛋白。人类HJV、HFE或TfR 2基因的突变降低铁调素表达并引起遗传性血色病。相反，间质蛋白酶-2（MT 2）是铁调素表达的稳健抑制剂。人类MT 2基因突变导致铁调素表达增加，从而导致铁难治性缺铁性贫血。然而，再生蛋白诱导、MT 2抑制和铁调节铁调素表达的确切机制知之甚少。我们的长期目标是了解系统铁稳态的机制.本研究的目的是描述再生蛋白、MT 2和肝细胞生长因子激活物抑制剂-2（HAI-2）在铁调素表达调控中的协调作用。我们的中心假设是，再生蛋白作为一个支架，以促进hepcidin在肝细胞中的表达，和身体铁负荷负调节MT 2活性通过HAI-2调整hepcidin的表达到一个适当的水平。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，将通过追求两个特定目标来测试该假设：1）确定肝再生蛋白促进铁调素表达的潜在机制。2)测试MT 2与HAI-2协调以响应于身体铁负荷调节铁调素表达的假设。该方法是创新的，因为它专注于再生蛋白，MT 2和HAI-2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。

This proposal targets the molecular basis of iron overload disorders and iron-restricted anemia, which are among the most common hematological diseases worldwide. Recent studies have documented the iron-regulatory hormone hepcidin as the key molecule responsible for systemic iron homeostasis. Hepcidin expression is mediated via the bone morphogenetic protein signaling pathway and requires the involvement of other key plasma membrane proteins, including hemojuvelin (HJV), hemochromatosis protein (HFE), transferrin receptor-2 (TfR2), and neogenin. Mutations in the HJV, HFE, or TfR2 genes in humans reduce hepcidin expression and cause hereditary hemochromatosis. Conversely, matriptase-2 (MT2) is a robust suppressor for hepcidin expression. Mutations in the MT2 gene in humans result in increased hepcidin expression, which leads to iron-refractory iron-deficiency anemia. However, the precise mechanisms by which neogenin induces, MT2 suppresses, and iron modulates hepcidin expression are poorly understood. Our long- term goal is to understand the mechanism of systemic iron homeostasis. The objective of this grant is to characterize the coordination of neogenin, MT2, and the hepatocyte growth factor activator inhibitor-2 (HAI-2) in the regulation of hepcidin expression. Our central hypothesis is that neogenin acts as a scaffold to facilitate hepcidin expression in hepatocytes, and that bodily iron load negatively regulates MT2 activity through HAI-2 to 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 anemia. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Determine the underlying mechanism by which hepatic neogenin facilitates hepcidin expression. 2) Test the hypothesis that MT2 coordinates with HAI-2 to modulate hepcidin expression in response to bodily iron load. The approach is innovative, because it focuses on the mechanistic studies of neogenin, MT2, and HAI-2 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.