INTERMEDIATE FILAMENT EXPRESSION IN ASTROCYTES

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 我们之前已经报道过一些星形胶质细胞可以表达VCAM-1和外周蛋白，这是一种通常在外周神经元中发现的中间细丝。我们还发现，MCP-3在接近血脑屏障的同时表达上调。我们的假设是，这些星形胶质细胞被病毒感染的细胞激活，是脑炎发展的催化剂。使用体外和体外模型，我们检测了星形胶质细胞外周蛋白表达增加的时间以及伴随的趋化因子的分泌。星形胶质细胞GFAP表达降低，与外周蛋白升高一致。此时，它们也在积极分泌趋化因子MCP-3。这种趋化因子对于单核细胞向脑内的迁移和伴随的血脑屏障的破坏是重要的。因此，MCP-3在神经发病机制中具有重要作用。星形胶质细胞与SIV感染的巨噬细胞孵育后，S100B蛋白的表达也增加。“冷追逐”研究表明，星形胶质细胞有能力恢复到低外周蛋白、高GFAP中间丝和低表达炎性细胞因子/趋化因子的自然状态。因此，炎症刺激对于导致血脑屏障破坏的介质的产生是必要的和充分的。星形胶质细胞具有表达这种和其他中间纤维的可塑性。这与脑炎和血脑屏障破坏的生物相关趋化因子的合成和分泌不谋而合。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We have previously reported that a number of astrocytes can express VCAM-1 and peripherin, an intermediate filament normally found in peripheral neurons. We have also shown that MCP-3 is upregulated close to the blood-brain barrier at the same time. Our hypothesis was that these astrocytes had been activated by viral-infected cells and were a catalyst for the development of encephalitis. Using ex vivo and in vitro models, we examined the timing of increased expression of peripherin in astrocytes, and the concomitant secretion of chemokines. Astrocytes had decreased GFAP expression coincident with increased peripherin. At this time, they were also actively secreting the chemokine MCP-3. This chemokine is important for monocyte migration into brain and the concomitant disruption of the BBB. Thus, MCP-3 is important in neuropathogenesis. It was noted that astrocytes also had increased expression of S100b protein following incubation with SIV infected macrophages. "Cold chase" studies revealed that astrocytes have the capacity to revert to their native state of low peripherin with high GFAP intermediate filaments and low expression of inflammatory cytokines / chemokines. Thus, the inflammatory stimulus is necessary and sufficient for the production of mediator the leads to BBB disruption. Astrocytes have a plasticity of expression of this and other intermediate filaments. This coincides with the synthesis and secretion of biologically relevant chemokines for the development of encephalitis and disruption of the blood-brain barrier.