ROLE OF INTEGRINS IN MYELINATION

整合素在髓鞘形成中的作用

• 批准号: 6112524
• 负责人: JAMES L SALZER
• 金额: $ 17.54万
• 依托单位: MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6112524
• 关键词: Schwann cells; antireceptor antibody; antisense nucleic acid; cytoskeletal proteins; gene expression; immunofluorescence technique; immunoprecipitation; integrins; intermediate filaments; laboratory rat; myelination; neural cell adhesion molecules; oligodendroglia; recombinant DNA; transfection; western blottings

Striking changes in the morphology and differentiation of Schwann cells and oligodendrocytes occur during myelination. These events are likely to be regulated by adhesion molecules that are expressed at the surface of these cells and involve dramatic change in the organization of the cytoskeleton. In the peripheral nervous system contact with the basal lamina regulates Schwann cell ensheathment and myelination of axons. The molecular mechanism(s) by which the basal lamina promotes myelination is not known but is likely to reflect the activity of integrins expressed by Schwann cells. We have recently found that there is a dramatic change in the pattern of integrin expression during Schwann cell myelination, from alpha6beta1 to alpha6beta4, which is regulated by axonal contact. These findings, in turn, suggest that there is a transition in the transmembrane linkage of the Schwann cell with extracellular matrix from actin filaments in ensheathing cells to intermediate filaments in myelinating cell and have important implication for the dramatic morphologic changes of myelination. By contrast, very little is known about the expression or role of integrins in oligodendrocytes and their precursors and whether their expression is similarly regulating during differentiation. To continue our studies on the role of integrins in myelination we propose to; i) inhibit the function and modulate the expression of the major Schwann cell integrins using antibodies and recombinant DNA strategies respectively and then determine the consequence of these perturbations on myelin formation in vitro ii) characterize the reorganization of the Schwann cell cytoskeleton, with a particular emphasis on intermediate filaments and a unique intermediate filament associated protein, skelemin, during myelination, and iii) characterize the expression of beta1 integrins at different stages of the oligodendroglia lineage. Oligodendrocyte progenitors will be grown in different tissue culture conditions to regulate their differentiation; mature oligodendrocytes will be isolation by a novel method using the MBP promoter to drive the expression of a selectable marker. The effect of anti-beta1 antibodies on oligodendrocyte myelination in cocultures will also be assessed. These studies would provide important new insights into tahe molecular mechanisms by which integrins regulate the migration and differentiation of myelinating glial cell.

Schwann细胞的形态和分化的显着变化以及 髓鞘中发生少突胶质细胞。 这些事件可能是 由在这些表面表达的粘附分子调节 细胞并涉及细胞骨架组织的急剧变化。 在周围神经系统中与基底层的接触 Schwann细胞的包裹和轴突的髓鞘形成。 分子 基底层促进髓鞘的机制未知 但很可能反映了Schwann表达的整联蛋白的活性 细胞。 我们最近发现，这种变化发生了巨大变化 schwann细胞髓鞘中整联蛋白表达的模式，从 alpha6beta1 to alpha6beta4，由轴突接触调节。 这些 结果反过来表明，跨膜有过渡 Schwann细胞与肌动蛋白细胞外基质的连接 在看到髓细胞中间丝中的细胞中，有 对髓鞘形成的戏剧性形态变化的重要意义。 相比之下，对整合素的表达或作用知之甚少 在少突胶质细胞及其前体中，它们的表达是否为 在分化过程中类似地调节。 继续我们的研究 我们建议的整合素在髓鞘中的作用； i）抑制功能 并使用主要的Schwann细胞整合蛋白的表达 抗体和重组DNA策略，然后确定 这些扰动对体外髓磷脂形成的结果） 表征Schwann细胞细胞骨架的重组， 特别强调中间丝和独特的中间体 细丝相关的蛋白质，skelemin，在髓鞘中，III） 表征beta1整联蛋白在不同阶段的表达 少突endroglia谱系。 少突胶质细胞将生长 不同的组织培养条件以调节其分化； 成熟的少突胶质细胞将通过使用MBP的新方法隔离 启动子驱动可选标记的表达式。 效果 抗BETA1抗体在共培养中的少突胶质细胞髓鞘中将 也可以评估。 这些研究将为您提供重要的新见解 tahe分子机制，整联蛋白调节迁移和 骨髓神经胶质细胞的分化。