ROLES OF NEOGENIN AND MATRIPTASE-2 IN IRON HOMEOSTASIS

这项建议针对的是铁超载障碍和铁限制贫血的分子基础，这两种疾病是世界上最常见的血液疾病之一。最近的研究证明，铁调节激素海普西丁是负责全身铁稳态的关键分子。海普西丁的表达是通过骨形态发生蛋白信号通路介导的，需要其他关键质膜蛋白的参与，包括血色素沉着蛋白(HJV)、血色素沉着蛋白(HFE)、转铁蛋白受体2(TfR2)和新生蛋白。人类HJV、HFE或TfR2基因突变会减少海普西丁的表达，并导致遗传性血色素沉着症。相反，Mattritase-2(MT2)是一种强大的海普西丁表达抑制因子。人类MT2基因突变会导致海普西丁表达增加，从而导致铁耐受性缺铁性贫血。然而，新生素诱导、MT2抑制和铁调节海普西丁表达的确切机制尚不清楚。我们的长期目标是了解全身性铁稳态的机制。这项资助的目的是研究新生素、MT2和肝细胞生长因子激活物抑制物-2(HAI-2)在调节海普西丁表达中的协调作用。我们的中心假设是，新生素作为一种支架促进了肝细胞中海普西丁的表达，而体内铁负荷通过HAI-2负向调节MT2的活性，从而将海普西丁的表达调节到适当的水平。这一假设是根据申请者和其他实验室提供的数据提出的。这项拟议研究的基本原理是，了解铁对海普西丁表达的调节，有可能开发出治疗铁超载障碍和铁限制性贫血的新疗法。在强大的初步数据的指导下，这一假说将通过追求两个特定的目标来检验：1)确定肝脏新生激素促进海普西丁表达的潜在机制。2)验证MT2与HAI-2配位以调节海普西丁表达以响应体内铁负荷的假设。这种方法是创新的，因为它集中在分子、细胞和系统水平上研究新生素、MT2和HAI-2在铁调控的海普西丁表达中的机制。这项拟议的研究具有重要意义，因为它有望为药物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性铁平衡机制的理解，也将为将这些进展转化为铁紊乱患者的切实好处奠定基础。

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.