Investigation of hepcidin in mammalian iron homeostasis

描述(由申请人提供)： 海普西丁是一种抗菌肽，由肝脏合成，以应对炎症和铁超载。新的数据表明，海普西丁是小鼠和人体内铁稳态的主要调节因子。不适当的海普西丁表达与遗传性血色素沉着症和慢性病的贫血等疾病有关。这项建议旨在检验这一假说，即海普西丁是铁平衡的重要调节因子，与肠细胞、巨噬细胞和胎盘合体滋养层细胞结合，在这些细胞中它负向调节铁的外流。只有在整个动物的背景下，才能充分描述免疫系统与铁的储存和利用部位之间的联系。这项建议的具体目的是：1)建立四环素调控的海普西丁转基因小鼠，研究海普西丁活性在铁稳态和分布中的作用；2)确定海普西丁在小鼠中的过度表达是否能产生可靠的人类慢性病贫血模型；3)鉴定可能的海普西丁受体，以研究海普西丁如何调节细胞铁外流。KO1奖将在铁代谢和老鼠遗传学专家南希·安德鲁斯博士的指导下为候选人提供指导研究经验。在安德鲁斯博士的指导下，候选人将发展必要的技术技能和知识基础，以开发转基因和敲除小鼠，然后测试研究铁代谢生理学的假说。候选人还将有机会通过会见知名科学家，发表演讲，并为同行评议的期刊撰写关于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交界处的独立研究生涯。未来的工作将集中在研究海普西丁受体及其同系物在铁代谢和慢性病贫血中的作用。

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