CELLULAR STRESS RESPONSE IN VIRAL ENCEPHALITIS

这项研究的总体目标是确定细胞的作用， 中枢神经系统病毒感染的应激反应 神经系统（CNS）使用犬瘟热病毒（CDV）脑炎作为 模型目标1将定义应激反应诱导的基础 CDV RNA代谢的改变，并证实了更广泛的适用性 这些现象使用麻疹病毒（MV）。72 kDa热休克的作用 蛋白（72 k HSP）作为CDV的转录辅因子， 细胞应激对CDV mRNA半衰期的影响 测定，以及细胞应激与MV mRNA代谢的相关性 记录在案。目的2：探讨HSP 70蛋白在心肌细胞中的原位作用 在应激介导的病毒感染表型改变中， 72 k和73 k HSP的翻译抑制。目标3将确定 应激诱导的CDV RNA代谢改变对病毒 表型在犬小脑外植体培养，细胞系统， 在生理上与CNS感染更相关。热疗和细胞因子 应激反应的诱导将被用来剖析矛盾的 72 k HSP的细胞保护作用与细胞凋亡的关系 促进病毒感染。72 k HSP在肿瘤中的作用 介导这些应激反应介导的事件将由 反义抑制72 k HSP表达。未来的体内研究可以 确定免疫清除机制如何调节病毒的结果- 应激反应相互作用确立保护或有害作用 病毒性脑炎中枢神经系统应激反应的研究将为 基于HSP调节的治疗干预。

The overall goal of the research is to define the role of the cellular stress response in the modulation of viral infection of the central nervous system (CNS) using canine distemper virus (CDV) encephalitis as a model. Objective 1 will define the basis for stress response-induced alterations in CDV RNA metabolism and confirm the broader applicability of these phenomenon using measles virus (MV). The role of 72kDa heat shock protein (72k HSP) as a transcriptional cofactor for CDV will be established, the effect of cellular stress on CDV mRNA half life determined, and the relevance of cellular stress to MV mRNA metabolism documented. Objective 2 will establish the in situ role of HSP7O proteins in stress-mediated alterations of virus infection phenotype using translational inhibition of 72k and 73k HSP. Objective 3 will determine the effect of stress-induced alterations in CDV RNA metabolism on viral phenotype in canine cerebellar explant cultures, a cell system which is physiologically more relevant to CNS infection. Hyperthermic and cytokine induction of the stress response will be used to dissect the paradoxical relationship between the cytoprotective effects of 72k HSP and the promoting effects on virus infection. The specific role of 72k HSP in mediating these stress response-mediated events will be determined by antisense inhibition of 72k HSP expression. Future in vivo studies can determine how immune clearance mechanisms modulate the outcome of virus- stress response interaction. Establishing a protective or detrimental role of the CNS stress response in viral encephalitis will provide a basis for therapeutic intervention based upon HSP modulation.