STUDIES ON MYELIN PO PROTEIN--FUNCTION AND SORTING

髓磷脂PO蛋白的研究--功能与分类

• 批准号: 6240182
• 负责人: Marie T. Filbin
• 金额: $ 2.6万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 1997-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6240182
• 关键词: laboratory rabbit; laboratory rat; myelination; nerve /myelin protein; neural cell adhesion molecules; neurogenesis; peripheral nervous system; phosphorylation; protein biosynthesis; protein sequence; protein structure function

Compaction of the myelin membrane into lamellae is essential for its function as an insulator in axons of the peripheral nervous system (PNS). P(O), the most abundant glycoprotein in the PNS, is believed to hold these lamellae together. The long term goals of this study are to clarify in molecular terms the role of P(O) (as well as other proteins) in myelination in the hope of contributing to our understanding of the mechanisms of demyelinating diseases such as Guillain-Barre syndrome (GBS) and in neuronal regeneration in the PNS. The extracellular domains of P(O) undergo hemophilic P(O)P(O) interactions in which the carbohydrate moieties play a major role. Heterophilic interactions of P(O) with neurons are believed to promote neurite outgrowth. The overall goals of this proposal are to determine what roles various regions of P(O) play in the synthesis and compaction of myelin. Our adhesion assay specifically developed to identify extracellular regions of P(O) participating in interactions will be used to pursue the following aims. First, to determine by mutation whether a 5-amino acid sequenced in immunoglobulin-like domain of P(O) is crucial to adhesion. This sequence is also found in a flu virus vaccine which elicited GBS, therefore the results may also bear on the mechanisms of demyelination in this disease. Second, to clarify the role of the intracellular domain of P(O) in the adhesive properties of its extracellular domain and in the sorting of P(O) to myelin. Sorting will be assessed by expressing shark P(O) in rat Schwann cells, allowing myelination to occur, and determining by means of species-specific antibodies whether truncated forms of P(O) reach myelin. Third, to elucidate the interactions of P(O) with myelin associated glycoprotein, possibly in the initial stages of myelination, by mixed adhesion assays and by determining the adhesive properties of cells co-expressing both proteins. Fourth, to map the regions of P(O) that may be involved in heterophilic interactions with neurons by comparing the ability of cells expressing unaltered and mutated P(O) to promote neurite outgrowth. Accomplishment of these aims should substantially advance the long term understanding of the mechanism of myelin organization.

髓鞘膜致密成板层是其发生的关键 在周围神经系统(PNS)的轴突中起绝缘体的作用。 P(O)是三叉神经节中含量最丰富的糖蛋白，据信 这些薄片连在一起。这项研究的长期目标是 从分子角度阐明P(O)(以及其他蛋白质)的作用 在髓鞘形成过程中，希望有助于我们理解 格林-巴利综合征等脱髓鞘疾病的发病机制 (GBS)和三叉神经节神经元再生。胞外结构域 P(O)发生血友病P(O)P(O)相互作用 碳水化合物起着主要作用。的异嗜性相互作用 P(O)与神经元结合被认为促进了轴突的生长。整体而言 这项提案的目标是确定不同地区的 P(O)在髓鞘的合成和致密中起作用。我们的黏附试验 专为鉴定P(O)的胞外区而开发 参与互动将被用来实现以下目标。 首先，通过突变来确定一个5-氨基酸是否在 P(O)的免疫球蛋白样结构域是黏附的关键。此序列 在一种引起GBS的流感病毒疫苗中也发现了这种病毒，因此 这些结果也可能与这种疾病的脱髓鞘机制有关。 第二，阐明P(O)的胞内结构域在 其胞外区的粘附性及其在分选中的应用 P(O)为髓磷脂。通过在大鼠体内表达鲨鱼P(O)来评估分类 雪旺细胞，允许髓鞘形成，并通过 P(O)截短型是否达到物种特异性抗体 髓鞘。第三，阐明P(O)与髓鞘的相互作用 相关的糖蛋白，可能在髓鞘形成的初始阶段， 通过混合黏附试验和通过测定 细胞同时表达这两种蛋白质。第四，绘制P(O)的区域图 可能通过以下途径参与与神经元的异嗜性相互作用 表达未改变和突变P(O)的细胞对 促进轴突生长。实现这些目标应该 实质上促进了对其机制的长期理解 髓鞘组织。