Structural and Functional Studies of Iron Transport and Homeostasis

铁转运和稳态的结构和功能研究

• 批准号: 7895548
• 负责人: CHARLES MARTIN LAWRENCE
• 金额: $ 24.42万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895548
• 关键词: Anemia; Binding; Biochemical; Cirrhosis; Defect; Diabetes Mellitus; Disease; Face; Family; Fluorescence; Goals; Grant; Heme; Hereditary hemochromatosis; Homeostasis; Human; In Transferrin; Intervention; Investigation; Iron; Iron Overload; Malignant neoplasm of liver; Membrane; Metabolism; Mutagenesis; Neurodegenerative Disorders; Oxidoreductase; Pharmacotherapy; Population; Predisposition; Primary carcinoma of the liver cells; Proteins; Stroke; Structure; Structure-Activity Relationship; Transferrin; Transmembrane Domain; extracellular; genetic variant; glycosylation; insight; iron (III) reductase; mortality; mutant; oxidation; public health relevance; structural biology; therapy development; uptake

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.

描述（由申请人提供）：铁转运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，导致铁过载（遗传性血色病）易感性的遗传变异在某些人群中非常普遍。作为发展铁缺乏和铁过载治疗的必要步骤，我们的长期目标是实现对铁转运和体内平衡的更好的生化和结构理解。铁的跨膜转运基本上依赖于蛋白质还原酶，其将铁转化或维持在正确的氧化态以用于转运。铁还原酶和铁还原的机制因此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的药物干预提供靶点。我们建议Steap家族的金属还原酶，这最近被牵连在铁的运输和稳态的功能和结构的研究相结合。这些研究将为转铁蛋白循环中的铁摄取机制提供深入的了解，并且似乎与非转铁蛋白结合的铁摄取机制也相关。公共卫生关系：这项研究将调查铁转运和稳态的结构生物学，重点是金属还原酶的Steap家族。导致铁不足或过量的铁稳态缺陷与许多疾病状态相关，包括肝硬化、一般癌症和特别是肝细胞癌、糖尿病、贫血和铁过载、中风和各种神经退行性疾病。由于这个原因，Steap蛋白代表了多种人类疾病中药物治疗的潜在靶点。