Investigation of hepcidin in mammalian iron homeostasis

描述（由申请人提供）： 铁调素是一种抗微生物肽，由肝脏合成，以应对炎症和铁过载。新的数据表明铁调素是小鼠和人类体内铁稳态的主要调节因子，铁调素的不适当表达与遗传性血色素沉着症和慢性疾病贫血等疾病有关。该提议旨在检验铁调素是铁平衡的重要调节剂的假设，铁调素结合肠细胞、巨噬细胞和胎盘合胞体滋养层，其中铁调素负调节铁排出。只有在整个动物的情况下，免疫系统和铁储存和利用的网站之间的通信才能得到充分的表征。本发明的具体目的是：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）确定铁调素在小鼠中的过表达是否产生人类慢性疾病贫血的可靠模型，3）鉴定推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，候选人将发展必要的技术技能和知识基础，用于开发转基因和敲除小鼠，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界面的独立研究生涯。未来的工作将集中在铁调素受体及其同源物在铁代谢和慢性疾病贫血中的作用研究

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