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。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 表示子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 我们以前曾报道，一些星形胶质细胞可以表达VCAM-1和外周蛋白，一种通常在外周神经元中发现的中间丝。我们还表明，MCP-3在接近血脑屏障的同时上调。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。使用离体和体外模型，我们研究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分泌。星形胶质细胞GFAP表达减少，同时外周蛋白表达增加。在这个时候，他们也积极分泌趋化因子MCP-3。这种趋化因子对于单核细胞迁移到脑中以及伴随的BBB破坏是重要的。因此，MCP-3在神经发病机制中是重要的。注意到星形胶质细胞在与SIV感染的巨噬细胞孵育后也具有增加的S100 b蛋白表达。“冷追踪”研究揭示星形胶质细胞具有恢复到其具有高GFAP中间丝和低表达炎性细胞因子/趋化因子的低外周蛋白的天然状态的能力。因此，炎症刺激是必要的，足以产生介质，导致血脑屏障破坏。星形胶质细胞具有表达这种纤维和其他中间纤维的可塑性。这与脑炎发展和血脑屏障破坏的生物学相关趋化因子的合成和分泌相一致。

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.