IMMUNOGENETICS OF RESISTANCE/SUSCEPTIBILITY TO TMEV-INDUCED DEMYELINATION

该项目旨在识别和分析 影响不同品系小鼠易感性差异的基因 Theiler小鼠脑脊髓炎病毒（TMEV）诱导的脱髓鞘 疾病 TMEV诱导的脱髓鞘疾病提供了一个很好的模型 对于人类多发性硬化症（MS），无论是在临床症状的水平， 和组织病理学。 疾病是由活跃的细胞引起的- 介导的免疫反应，可能是迟发型超敏反应， 这种病毒会导致“无辜的旁观者”破坏髓鞘。 像人类MS一样，有一个明显的遗传影响的可能性， 疾病发展，以及相关基因的鉴定/分析 可能提供机制（包括预防或缓解）的线索 和其他风险因素。 这些将特别相关， 已知等同的人类基因与在以下文献中定义的那些相关： 这些研究。 分析将沿着沿着三条调查路线进行。 首先是 使用遗传分析的经典方法，涉及世代和 感病品种与感病品种杂交F_1、F_2及回交后代研究 抗性菌株，以确定哪个性状是显性的，并使一个 相关分离基因座数目的最小估计。 后续 使用同源的、重组的、突变的和重组-近交的菌株将 有助于鉴定和绘制所涉及的基因座。 第二阶段是分析是否有抗药性的动物未能发展 疾病，因为（a）他们本质上不能产生 针对TMEV的破坏性免疫反应，或者（2）它们是否主动 抑制潜在的反应，如果从这些抑制释放， 机制，会继续导致疾病。 第三阶段是发展RFLP分析方法，用于分析 参与TMEV诱导的脱髓鞘疾病的特异性基因， 可能的预测用途，以确定哪些动物，在隔离 这些人，都有患上这种疾病的高风险。

This project is directed toward the identification and analysis of the genes affecting the differential susceptibility of different mouse strains to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. TMEV-induced demyelinating disease provides an excellent model for human multiple sclerosis (MS), both at the level of clinical symptoms and of histopathology. The disease occurs as the result of an active cell- mediated immune response, probably delayed type hypersensitivity, against the virus, which results in "innocent bystander" destruction of myelin. Like human MS, there is a clear genetic influence on the likelihood of disease development, and the identification/analysis of the involved genes may provide clues as to mechanisms (including prevention or alleviation) and other risk factors. These will be especially relevant where the equivalent human genes are known which correlate with those defined in these studies. The analysis will proceed along three lines of inquiry. The first is the use of classical methods of genetic analysis, involving the generation and study of F1 and F2 hybrids and backcross progeny between susceptible and resistant strains to determine which trait is dominant and to make a minimal estimate of the number of relevant segregating loci. Subsequent use of congenic, recombinant, mutant and recombinant-inbred strains will aid in identification and mapping of the loci involved. The second phase is to analyze whether resistant animals fail to develop the disease because (a) they are intrinsically incapable of generating the destructive immune responses against TMEV, or whether (2) they actively inhibit latent responses which, if released from these inhibitory mechanisms, would go on to cause disease. The third phase is to develop RFLP assays for analyzing the roles of specific genes involved in TMEV-induced demyelinating disease and for possible predictive use in identifying which animals, among segregating populations, are at high risk for developing the disease.