ROLES OF NEOGENIN AND MATRIPTASE-2 IN IRON HOMEOSTASIS

这一建议的目标是铁超载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。最近的研究表明，铁调节激素hepcidin是负责全身铁稳态的关键分子。Hepcidin的表达通过骨形态发生蛋白信号通路介导，并需要其他关键质膜蛋白的参与，包括血幼蛋白（HJV）、血色素沉着蛋白（HFE）、转铁蛋白受体-2 （TfR2）和neogenin。人类HJV、HFE或TfR2基因的突变会降低hepcidin的表达并导致遗传性血色素沉着病。相反，基质酶-2 （MT2）是hepcidin表达的强大抑制因子。人类MT2基因突变导致hepcidin表达增加，从而导致铁难治性缺铁性贫血。然而，neogenin诱导、MT2抑制和铁调节hepcidin表达的确切机制尚不清楚。我们的长期目标是了解系统铁稳态的机制。该资助的目的是表征neogenin、MT2和肝细胞生长因子激活因子抑制剂-2 （HAI-2）在hepcidin表达调节中的协同作用。我们的中心假设是neogenin作为支架促进hepcidin在肝细胞中的表达，并且身体铁负荷通过HAI-2负性调节MT2活性，将hepcidin表达调节到适当水平。这一假设是根据申请人和其他实验室提供的数据制定的。这项研究的基本原理是，了解铁对hepcidin表达的调节，有可能开发出治疗铁超载疾病和铁限制性贫血的新疗法。在强有力的初步数据的指导下，这一假设将通过追求两个特定目标来验证：1)确定肝neogenin促进hepcidin表达的潜在机制。2)验证MT2与HAI-2协同调节hepcidin表达以应对机体铁负荷的假说。该方法是创新的，因为它侧重于在分子、细胞和系统水平上研究铁调节hepcidin表达的neogenin、MT2和HAI-2的机制。该研究具有重要意义，因为它有望为开发药理学策略提供基础。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，而且为将这些进展转化为铁疾病患者的切实益处奠定了基础。

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.