Investigation of hepcidin in mammalian iron homeostasis

铁调素在哺乳动物铁稳态中的研究

• 批准号: 6702747
• 负责人: Cindy Norene Roy
• 金额: $ 10.75万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-15 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6702747
• 关键词: anemia; antiinfective agents; biological models; chronic disease /disorder; enzyme linked immunosorbent assay; genetically modified animals; histology; immunocytochemistry; inflammation; iron; iron metabolism; laboratory mouse; liver; macrophage; model design /development; protein structure function; receptor; trophoblast

DESCRIPTION (provided by applicant): Hepcidin is an antimicrobial peptide that is synthesized by the liver in response to inflammation and iron overload. Emerging data implicate hepcidin as a major regulator of iron homeostasis in mouse and man. Inappropriate hepcidin expression is associated with diseases such as hereditary hemochromatosis and the anemia of chronic disease. This proposal is designed to test the hypothesis that hepcidin is an essential regulator of iron balance that binds to enterocytes, macrophages, and placental syncytiotrophoblasts where it negatively regulates iron egress. Only in the context of the whole animal can the communication between the immune system and sites of iron storage and utilization be adequately characterized. The Specific Aims of this proposal are: 1) to develop a tetracycline-regulated hepcidin transgenic mouse to investigate the role of hepcidin activity in iron homeostasis and distribution, 2) to determine whether over expression of hepcidin in mice produces a faithful model of the anemia of chronic disease in humans, 3) to identify the putative hepcidin receptor to investigate how hepcidin regulates cellular iron egress. The KO1 award will provide mentored research experience to the candidate under the guidance of Dr. Nancy Andrews, an expert in iron metabolism and mouse genetics. Under Dr. Andrews' mentorship, the candidate will develop the technical skills and the knowledge base necessary for developing transgenic and knock out mice and then testing hypotheses that investigate the physiology of iron metabolism. The candidate will also have the opportunity to develop her reputation as an independent contributor to the field by meeting with prominent scientists, delivering talks, and writing scientific articles about her findings for peer reviewed journals. The KO1 award will facilitate the candidate's transition to an independent research career at the interface of immunology and iron metabolism. Future work will focus on investigating the role of the hepcidin receptor and its homologs in iron metabolism and the anemia of chronic disease

描述（由申请人提供）： 铁调素是一种抗菌肽，由肝脏针对炎症和铁超载而合成。新数据表明铁调素是小鼠和人类铁稳态的主要调节剂。不适当的铁调素表达与遗传性血色素沉着症和慢性病贫血等疾病有关。该提案旨在检验以下假设：铁调素是铁平衡的重要调节剂，它与肠上皮细胞、巨噬细胞和胎盘合体滋养层细胞结合，对铁的排出产生负调节。只有在整个动物的背景下，才能充分表征免疫系统与铁储存和利用部位之间的通讯。该提案的具体目标是：1）开发四环素调节的铁调素转基因小鼠，以研究铁调素活性在铁稳态和分布中的作用，2）确定小鼠中铁调素的过度表达是否产生忠实的贫血模型人类慢性疾病的研究，3) 鉴定假定的铁调素受体，以研究铁调素如何调节细胞铁排出。 KO1 奖将在铁代谢和小鼠遗传学专家 Nancy Andrews 博士的指导下为候选人提供指导性研究经验。在安德鲁斯博士的指导下，候选人将培养开发转基因和基因敲除小鼠所需的技术技能和知识基础，然后测试研究铁代谢生理学的假设。候选人还将有机会通过与杰出科学家会面、发表演讲以及为同行评审期刊撰写有关她的发现的科学文章来发展她作为该领域独立贡献者的声誉。 KO1 奖将促进候选人过渡到免疫学和铁代谢领域的独立研究生涯。未来的工作将集中于研究铁调素受体及其同系物在铁代谢和慢性病贫血中的作用