CTL ESCAPE MUTANTS--ROLE IN MHV INDUCED DEMYELINATION

描述(申请者摘要)：应聘者加入 医学院的神经科学研究生学位课程已经 将人类疾病的临床知识与基础科学研究相结合。 博士阶段的培训部分将使候选人能够 在职业生涯中进行独立研究，希望有一天能包括 承担临床和实验室的责任。跨学科性质 神经科学项目提供了分子、细胞和 系统神经科学。该项目，涉及致病机制 病毒诱导的脱髓鞘，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 神经科学。这种不同学科的整合将在 未来从事神经科学研究和临床应用。在……里面 项目条款本身，用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，可导致急性脑炎和 慢性脱髓鞘。后者是人类的典范 脱髓鞘疾病，多发性硬化症。在提议的模型中，一个 感染MHV的小鼠有不同比例的保护 致死性急性脑炎，但后来发展为慢性脱髓鞘 有后肢瘫痪临床症状的脑脊髓炎。上一首 结果提示，临床疾病的发展数周 接种后部分是由于细胞毒性T细胞(CTL)的选择 逃离变种人。这项提案的目标是更明确地确定 CTL逃逸突变在慢性粒细胞白血病发病机制中的作用 脱髓鞘。为了实现这一目标，将有三个具体目标 开展：(1)确定感染变异病毒是否会导致 在慢性脱髓鞘的早期发展过程中 并以更高的频率接种；(2)评估 亚显性CD8+T细胞表位(S表位-598-605)在病毒持续和感染中的作用 慢性脱髓鞘；以及(3)确定为什么 免疫优势CD8+T细胞表位S-510-518的可能突变为 在持续感染期间选择。持续感染的小鼠 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.