Structural and Functional Studies of Iron Transport and Homeostasis

说明(申请人提供)：铁运输和新陈代谢疾病是导致人类痛苦和死亡的最常见原因之一。全世界有10多亿人缺铁，导致铁超载(遗传性血色沉着症)易感性的基因变异在某些人群中非常普遍。作为开发铁缺乏和铁负荷治疗的必要步骤，我们的长期目标是更好地了解铁的运输和动态平衡的生化和结构。铁的跨膜运输在很大程度上依赖于蛋白质还原酶来转换或保持铁在正确的氧化状态下进行运输。因此，铁还原酶和铁还原机制值得深入研究，因为它们可能为药物干预提供促进或抑制细胞铁摄取的靶点。我们建议对STEAP金属还原酶家族进行功能和结构的结合研究，该家族最近被认为与铁的运输和动态平衡有关。这些研究将为深入了解转铁蛋白循环中铁摄取的机制提供帮助，并似乎与非转铁蛋白结合铁摄取机制有关。公共卫生相关性：这项拨款中提议的研究将调查铁运输和动态平衡的结构生物学，重点是STEAP金属还原酶家族。铁稳态的缺陷导致铁不足或过多，与许多疾病状态有关，包括肝硬变、癌症，特别是肝细胞癌、糖尿病、贫血和铁负荷过高、中风和各种神经退行性疾病。出于这个原因，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.