Isolation and Characterization of a Ferritin Receptor

描述(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，少突胶质细胞的代谢率相对较高，并且含有较高比例的铁需要酶。因此，这些细胞对铁的需求很高。的确，少突胶质细胞是大脑中铁染色的主要细胞。与少突胶质细胞对铁的高需求相一致的是，观察到髓鞘过少与铁缺乏有关，并且新生儿脑中铁摄取的峰值与髓鞘形成的开始相一致。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取铁的方式。大多数细胞，包括大脑中的神经元，通过细胞表面表达的转铁蛋白受体获得转铁蛋白提供的铁。然而，免疫组织化学和放射自显影显示，成熟的少突胶质细胞不表达转铁蛋白受体。通过原位杂交，即使在实验性缺铁期间，白质中也没有检测到转铁蛋白受体的mRNA。因此，少突胶质细胞必须有一个非转铁蛋白依赖的系统才能获得铁。我们有证据表明，铁蛋白受体选择性地表达在小鼠和人类的白质束中，并在细胞培养中表达少突胶质细胞。此外，在多发性硬化症的斑块附近，这些受体的表达发生了变化。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竞争铁。因此，这种应用的工作假设是，有一种铁蛋白结合蛋白由少突胶质细胞选择性表达，这是这些细胞获得铁的机制。该项目的目标是提纯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看法，并为少突胶质细胞生物学以及脱髓鞘疾病的诊断和治疗策略的研究开辟新的方向。

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