CTL ESCAPE MUTANTS--ROLE IN MHV INDUCED DEMYELINATION

描述（申请人的摘要）：候选人的目标，在加入 神经科学研究生学位课程从医学院一直到 将人类疾病临床知识与基础科学研究相结合。 博士学位的培训部分。阶段将使候选人能够 从事独立的研究，希望有一天能包括 临床和实验室职责。 涉及多学科 神经科学计划提供分子，细胞， 系统神经科学 该项目，涉及的发病机制， 病毒引起的脱髓鞘，提供了学习大量知识的机会， 关于分子生物学、免疫学和病毒学，并将它们与联合收割机结合起来， 神经科学 各种学科的这种整合将是有价值的， 在未来从事神经科学研究和临床应用。 在 项目本身的条款，小鼠肝炎病毒的信息，毒株 JHM（MHV-JHM）是一种嗜神经性冠状病毒，可导致急性脑炎， 慢性脱髓鞘 后者是人类的一种模式。 脱髓鞘疾病多发性硬化症 在该模型中，A 不同百分比的MHV感染小鼠受到保护， 致命的急性脑炎，但后来发展为慢性脱髓鞘 脑脊髓炎伴后肢瘫痪的临床体征。 先前 结果表明，临床疾病的发展数周 部分原因是由于细胞毒性T细胞（CTL）的选择 逃跑变种人 本提案的目的是更明确地确定 CTL逃逸突变体是否有助于慢性 脱髓鞘 为了实现这一目标，将有三个具体目标： （1）确定感染变异病毒是否导致 在慢性脱髓鞘的早期发展中， 接种和更高的频率;（2）评估的作用， 亚显性CD 8 + T细胞表位（表位S-598-605）在病毒持久性和 慢性脱髓鞘;和（3）为了确定为什么只有一个子集的所有 免疫显性CD 8 + T细胞表位S-510-518中可能的突变是 在持续感染期间选择。 小鼠持续感染 MHV-JHM作为分析CTL逃逸意义的模型系统 突变体及其与脱髓鞘发病机制的相关性。

DESCRIPTION (Applicant's Abstract): The candidate's goal in joining the neuroscience graduate degree program from medical school has been to integrate clinical knowledge of human disease with basic science research. The training component of the Ph.D. phase will enable the candidate to conduct independent research in a career that one day will hopefully include both clinical and laboratory responsibilities. The interdisciplinary nature of the neuroscience program provides experience in molecular, cellular, and systems neuroscience. The project, involving the pathogenesis of viral-induced demyelination, affords the opportunity to learn a great deal about molecular biology, immunology and virology, and combine them with neuroscience. This integration of various disciplines will be valuable in pursuing neuroscience research and clinical applications in the future. In terms of the project itself, information with mouse hepatitis virus, strain JHM (MHV-JHM), a neurotropic coronavirus, results in acute encephalitis and chronic demyelination. The latter serves as a model for the human demyelinating disease, multiple sclerosis. In the proposed model, a variable percentage of MHV-infected mice are protected from an otherwise fatal acute encephalitis but later develop a chronic demyelinating encephalomyelitis with clinical signs of hindlimb paralysis. Previous results suggested that the development of clinical disease several weeks after inoculation was in part due to the selection of cytotoxic T-cell (CTL) escape mutants. The goal of this proposal is to determine more definitively whether CTL escape mutants contribute to the pathogenesis of chronic demyelination. In order to achieve this, three specific aims will be undertaken: (1) To determine whether infection with variant virus results in the development of chronic demyelination at earlier times after inoculation and with a higher frequency; (2) To assess the role of the subdominant CD8+ T-cell epitope (epitope S-598-605) in viral persistence and chronic demyelination; and (3) To determine why only a subset of all possible mutations in the immunodominant CD8+ T-cell epitope S-510-518 are selected during persistent infection. Mice persistently infected with MHV-JHM serve as a model system for analyzing the significance of CTL escape mutants and their relevance to the pathogenesis of demyelination.