ROLES OF NEOGENIN AND MATRIPTASE-2 IN IRON HOMEOSTASIS

Neogenin 和 Matriptase-2 在铁稳态中的作用

• 批准号: 10555315
• 负责人: An-Sheng Zhang
• 金额: $ 51.34万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555315
• 关键词: Anemia; Animal Model; BMP2 gene; Binding; Bone Marrow; Bone Morphogenetic Proteins; Catalytic Domain; Cell membrane; Cell surface; Cells; Complex; Cytoplasmic Tail; Data; Development; Disease; Duodenum; Enzyme Precursors; Erythrocytes; Family member; Foundations; Genes; Goals; Grant; HFE2 gene; Hematological Disease; Hemochromatosis; Hepatic; Hepatocyte; Hereditary hemochromatosis; Homeostasis; Hormones; Human; Integral Membrane Protein; Intervention; Iron; Iron Metabolism Disorders; Iron Overload; Iron deficiency anemia; Knockout Mice; Knowledge; Laboratories; Life; Ligands; Liver; Maintenance; Mediating; Membrane; Membrane Proteins; Mission; Modeling; Molecular; Molecular Target; Mus; Mutation; Neurons; Normal Range; Nutrient; Outcome; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Plasma; Proteins; Public Health; Refractory; Regulation; Regulatory Pathway; Research; Role; Serine Protease; Signal Pathway; Signal Transduction; Signaling Protein; Spleen; Testing; Translating; Transmembrane Domain; United States National Institutes of Health; bone morphogenetic protein receptors; design; hepatocyte growth factor activator; hepcidin; inhibitor; innovation; matriptase 2; mouse model; mutant; neogenin; novel therapeutics; peptide hormone; pharmacologic; receptor; response; scaffold; sensor; transferrin receptor 2; trypsin-like serine protease; vector

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.

该提案针对铁超载疾病和铁限制性贫血的分子基础，这两种疾病是全世界最常见的血液疾病。最近的研究证明铁调节激素铁调素是负责全身铁稳态的关键分子。铁调素的表达通过骨形态发生蛋白信号通路介导，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 (TfR2) 和新生蛋白。人类 HJV、HFE 或 TfR2 基因突变会降低铁调素表达并导致遗传性血色素沉着症。相反，matriptase-2 (MT2) 是铁调素表达的强大抑制剂。人类 MT2 基因突变会导致铁调素表达增加，从而导致铁难治性缺铁性贫血。然而，人们对neogenin 诱导、MT2 抑制和铁调节hepcidin 表达的精确机制知之甚少。我们的长期目标是了解全身铁稳态的机制。本次资助的目的是表征 neogenin、MT2 和肝细胞生长因子激活剂抑制剂 2 (HAI-2) 在铁调素表达调节中的协调作用。我们的中心假设是，neogenin 作为支架促进肝细胞中 hepcidin 的表达，并且身体铁负荷通过 HAI-2 负向调节 MT2 活性，从而将 hepcidin 表达调整到适当的水平。这一假设是根据申请人和其他实验室产生的数据制定的。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，该假设将通过追求两个具体目标进行检验：1）确定肝脏新生蛋白促进铁调素表达的潜在机制。 2) 检验 MT2 与 HAI-2 协调调节铁调素表达以响应身体铁负荷的假设。该方法具有创新性，因为它侧重于在分子、细胞和系统水平上对neogenin、MT2 和HAI-2 在铁调节铁调素表达中的机制研究。拟议的研究意义重大，因为它有望为药理学策略的开发提供基础。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失调患者的切实益处奠定基础。

项目成果

A long sought after "receptor" for ERFE?

长期以来备受追捧的 ERFE“受体”？

• DOI: 10.1182/blood-2018-08-869586
• 发表时间: 2018
• 期刊: Blood
• 影响因子: 20.3
• 作者: Zhang,An-Sheng;Enns,CarolineA
• 通讯作者: Enns,CarolineA

The Tumor Suppressor, P53, Decreases the Metal Transporter, ZIP14.

• DOI: 10.3390/nu9121335
• 发表时间: 2017-12-08
• 期刊: Nutrients
• 影响因子: 5.9
• 作者: Zhao N;Zhang AS;Wortham AM;Jue S;Knutson MD;Enns CA
• 通讯作者: Enns CA

Matriptase-2 regulates iron homeostasis primarily by setting the basal levels of hepatic hepcidin expression through a nonproteolytic mechanism.

• DOI: 10.1016/j.jbc.2023.105238
• 发表时间: 2023-10
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Enns, Caroline A.;Weiskopf, Tyler;Zhang, Richard H.;Wu, Jeffrey;Jue, Shall;Kawaguchi, Makiko;Kataoka, Hiroaki;Zhang, An-Sheng
• 通讯作者: Zhang, An-Sheng

Grab and go: transferrin uptake in erythropoiesis.

• DOI: 10.1182/blood.2022017638
• 发表时间: 2022-09
• 期刊: Blood
• 影响因子: 20.3
• 作者: An-Sheng Zhang;C. Enns

Neogenin Facilitates the Induction of Hepcidin Expression by Hemojuvelin in the Liver.

Neogenin 促进肝脏中血幼素诱导铁调素表达。

• DOI: 10.1074/jbc.m116.721191
• 发表时间: 2016
• 期刊: The Journal of biological chemistry
• 作者: Zhao,Ningning;Maxson,JuliaE;Zhang,RichardH;Wahedi,Mastura;Enns,CarolineA;Zhang,An-Sheng
• 通讯作者: Zhang,An-Sheng