Structural and Functional Studies of Iron Transport and Homeostasis

描述（由申请人提供）：铁运输和代谢疾病是人类痛苦和死亡的最常见原因之一。全世界有超过10亿人缺铁，导致铁超载易感性的遗传变异（遗传性血色素沉着症）在一些人群中非常普遍。作为铁缺乏和铁超载治疗发展的必要步骤，我们的长期目标是实现对铁运输和体内平衡的更大的生化和结构理解。铁的跨膜运输在很大程度上依赖于蛋白质还原酶，蛋白质还原酶将铁转化或维持在正确的氧化状态以进行运输。因此，铁还原酶和铁还原机制值得进行重要的研究，因为它们可能为促进或抑制细胞铁摄取提供药物干预的靶点。我们建议对Steap家族的金属还原酶进行功能和结构的结合研究，该家族最近与铁运输和体内平衡有关。这些研究将深入了解转铁蛋白循环中铁摄取的机制，并与非转铁蛋白结合的铁摄取机制相关。公共卫生相关性：本基金提出的研究将调查铁运输和体内平衡的结构生物学，重点是Steap金属还原酶家族。铁体内平衡缺陷导致的铁不足或过量与一系列疾病状态有关，包括肝硬化、癌症，特别是肝细胞癌、糖尿病、贫血和铁超载、中风和各种神经退行性疾病。因此，Steap蛋白代表了多种人类疾病药物治疗的潜在靶点。

DESCRIPTION (provided by applicant): Diseases of iron transport and metabolism are among the most prevalent causes of human suffering and mortality. Greater than one billion people throughout the world are iron deficient and genetic variants conferring susceptibility to iron overload (hereditary hemochromatosis) are highly prevalent in some populations. As a necessary step in the development of treatments for iron deficiency and iron overload, our long-term goals are to achieve greater biochemical and structural understanding of iron transport and homeostasis. The transport of iron across membranes is substantially dependent upon protein reductases that convert or maintain iron in the correct oxidation state for transport. Ferric reductases and mechanisms of iron reduction are thus worthy of significant investigation as they may provide targets for pharmacological intervention to either promote or inhibit cellular iron uptake. We propose a combination of functional and structural studies on the Steap family of metalloreductases, which have been recently implicated in iron transport and homeostasis. These studies will provide insight into the mechanism of iron uptake in the transferrin-cycle, and appear relevant to the mechanisms of non-transferrin bound iron uptake as well. PUBLIC HEALTH RELEVANCE: The studies proposed in this grant will investigate the structural biology of iron transport and homeostasis, with an emphasis on the Steap family of metalloreductases. Defects in iron homeostasis leading to insufficient or excess iron are relevant to a slew of disease states, including cirrhosis of the liver, cancer in general and hepatocellular carcinoma in particular, diabetes, anemia and iron overload, stroke and various neurodegenerative diseases. For this reason, the Steap proteins represent potential targets of drug therapy in a variety of human disorders.