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Molecular Mechanisms of Iron Homeostasis

铁稳态的分子机制

基本信息

批准号：
9209483
负责人：
Aashish Manglik
金额：
$ 39.25万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-19 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9209483
关键词：
Anemia Binding Biochemical Biological Assay Blood Cardiomyopathies Cellular biology Chronic Complex Data Development Diabetes Mellitus Disease Down-Regulation Drug Targeting Electron Spin Resonance Spectroscopy Enterocytes Environment Erythrocytes Erythropoiesis Failure Family Fluorescence Foundations Functional disorder Hemochromatosis Homeostasis Hormones Human Inflammation Inherited Integral Membrane Protein Ions Iron Iron Metabolism Disorders Iron Overload Iron deficiency anemia Kidney Diseases Lipids Liver Cirrhosis Mediating Methods Modeling Molecular Mutation Pancreas Pathway interactions Physiology Play Preparation Protein Engineering Proteins Recycling Regulation Research Role Secondary to Serum Serum iron level result Structure Techniques Therapeutic Tissues Work X-Ray Crystallography base biophysical analysis biophysical techniques cofactor drug discovery hepcidin high throughput screening human disease innovation insight iron deficiency iron metabolism iron supplementation macrophage metal transporting protein 1 mouse model novel novel strategies novel therapeutic intervention novel therapeutics oxidative damage prevent programs reconstitution therapeutic target therapy development tool uptake

项目摘要

PROJECT SUMMARY Transmembrane proteins play critically important roles in human physiology and disease. Among the many roles of such transmembrane proteins is the regulation of serum iron concentration. Iron levels must be maintained at sufficient levels to support erythropoiesis; failure to do so results in iron deficiency anemia. Conversely, iron overload secondary to the inherited diseases of hemochromatosis results in liver cirrhosis, diabetes, and cardiomyopathy. Serum iron levels are tightly controlled by the protein hormone hepcidin, which induces degradation of the iron efflux transporter ferroportin and thereby prevents uptake of iron from enterocytes and recycling of iron from macrophages. However, the molecular basis of ferroportin function and its regulation by hepcidin remains poorly characterized. The proposed research will elucidate the biochemical, structural, and biophysical basis of ferroportin activity and will develop new ways of modulating ferroportin function. These studies will develop novel strategies for treating diseases resulting from dysregulation of iron homeostasis. More broadly, elucidating the molecular basis of ferroportin function will yield general insights into the Major Facilitator Superfamily of transporters, a large group of transmembrane proteins responsible for many disease states.

项目总结跨膜蛋白在人体生理和疾病中起着至关重要的作用。在这些人中这种跨膜蛋白的许多作用是调节血清铁浓度。铁水平必须维持在足够的水平以支持红细胞生成；否则会导致铁缺乏性贫血。相反，铁超载继发于遗传性疾病血色沉着症会导致肝硬变、糖尿病和心肌病。血清铁水平是受到蛋白质荷尔蒙海普西丁的严格控制，这种激素可以导致铁外流的降解转运铁蛋白，从而阻止从肠细胞摄取铁和从肠细胞回收铁巨噬细胞。然而，铁蛋白功能的分子基础及其受海普西丁的调节仍然没有很好的特征。这项拟议的研究将阐明生物化学、结构和铁蛋白活性的生物物理基础，并将开发新的途径来调节铁蛋白的功能。这些研究将开发治疗由铁调节失调引起的疾病的新策略。动态平衡。更广泛地说，阐明铁蛋白功能的分子基础将产生一般的对主要促进型转运蛋白超家族--一大群跨膜蛋白的洞察导致许多疾病状态的蛋白质。