Isolation and Characterization of a Ferritin Receptor

铁蛋白受体的分离和表征

• 批准号: 6807498
• 负责人: JAMES Robert CONNOR
• 金额: $ 17.31万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6807498
• 关键词: binding proteins; brain; clinical research; ferritin; human tissue; iron; molecular cloning; multiple sclerosis; myelination; oligodendroglia; postmortem; protein purification; protein structure function; receptor; receptor expression; tissue resource /registry

DESCRIPTION (provided by applicant): Iron is essential for numerous biosynthetic and metabolic activities in the brain. In the brain, oligodendrocytes have a relatively high metabolic rate and contain a high percentage of iron requiring enzymes. Consequently, these cells have a high demand for iron. Indeed, oligodendrocytes are the predominant cells to stain for iron in the brain. Consistent with the high iron requirements of oligodendrocytes are the observations that hypomyelination is associated with iron deficiency and peak iron uptake in the neonatal brain coincides with the onset of myelination. A significant unknown in the study of iron, oligodendrocytes and myelination is the means by which oligodendrocytes acquire iron. The majority of cells including neurons in the brain acquire iron delivered by transferrin through its receptor that is expressed on their cell surface. However, mature oligodendrocytes fail to express transferrin receptor based on both immunohistochemical data and autoradiography. The mRNA for transferrin receptors is not detected in white matter with in situ hybridization even during experimental iron deficiency. Therefore, oligodendrocytes must have a non-transferrin dependent system to obtain iron. We have evidence that receptors for ferritin are selectively expressed in white matter tracts in mice and humans and oligodendrocytes in cell culture. Furthermore, the expression of these receptors is altered in the vicinity of plaques in Multiple Sclerosis. The physiological advantage of expressing a receptor for ferritin is that oligodendrocytes do not have to compete with neurons for iron. Thus the working hypothesis for this application is that there is a ferritin binding protein that is selectively expressed by oligodendrocytes and that this is the mechanism by which these cells obtain iron. The goal of this project is to purify the ferritin receptor and clone the gene. This project will significantly alter our thinking on brain iron transport and open novel directions for research in oligodendrocyte biology and diagnositic and therapeutic strategies in demyelinating disorders

描述（由申请人提供）：铁是大脑中许多生物合成和代谢活动所必需的。在大脑中，少突胶质细胞具有相对较高的代谢率，并且含有高比例的需要铁的酶。因此，这些细胞对铁的需求量很大。的确，少突胶质细胞是大脑中主要的铁染色细胞。与少突胶质细胞的高铁需求一致的是，观察到低髓鞘形成与缺铁有关，新生儿大脑铁摄取高峰与髓鞘形成的发生一致。在铁、少突胶质细胞和髓鞘形成的研究中，一个重要的未知因素是少突胶质细胞获得铁的途径。包括大脑神经元在内的大多数细胞通过转铁蛋白受体在细胞表面表达获得铁。然而，成熟的少突胶质细胞根据免疫组织化学数据和放射自显影不能表达转铁蛋白受体。即使在实验缺铁期间，原位杂交在白质中也未检测到转铁蛋白受体的mRNA。因此，少突胶质细胞必须有一个不依赖转铁蛋白的系统来获取铁。我们有证据表明，铁蛋白受体在小鼠和人类的白质束和细胞培养中的少突胶质细胞中选择性表达。此外，这些受体的表达在多发性硬化症斑块附近发生改变。表达铁蛋白受体的生理优势是少突胶质细胞不必与神经元争夺铁。因此，这项应用的工作假设是，有一种铁蛋白结合蛋白被少突胶质细胞选择性地表达，这就是这些细胞获得铁的机制。本项目的目的是纯化铁蛋白受体并克隆该基因。该项目将显著改变我们对脑铁转运的认识，为少突胶质细胞生物学和脱髓鞘疾病的诊断和治疗策略的研究开辟新的方向