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

Neogenin 和 Matriptase-2 在血幼素介导的铁调素表达中的作用

基本信息

批准号：
8885941
负责人：
An-Sheng Zhang
金额：
$ 33.23万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8885941
关键词：
Address Adolescent Anemia Animal Model Blood Circulation Cells Cleaved cell Data Databases Development Disease Foundations Genes Goals Hematological Disease Hemochromatosis Heparan Sulfate Proteoglycan Hepatic Hepatocyte Hereditary hemochromatosis Homeostasis Hormones Human Integral Membrane Protein Intervention Iron Iron Metabolism Disorders Iron Overload Iron deficiency anemia Knowledge Laboratories Lead Life Ligands Link Liver Mediating Membrane Mission Modeling Molecular Molecular Target Mus Mutation Nutrient Outcome Pathogenesis Patients Play Process Proteins Public Health Recombinant adeno-associated virus (rAAV)Refractory Regulation Regulatory Pathway Research Role ST14 gene Serine Protease Signal Pathway Signal Transduction Testing Translating base bone morphogenetic protein 6 bone morphogenetic protein receptors design hepatocyte growth factor activator hepcidin in vivo inhibitor/antagonist innovation interest iron metabolism knock-down matriptase 2 mutant mouse model neogenin peptide hormone public health relevance receptor sensor tool transferrin receptor 2 vector

项目摘要

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.