IMMUNOGENETICS OF RESISTANCE/SUSCEPTIBILITY TO TMEV-INDUCED DEMYELINATION

该项目旨在识别和分析 影响不同品系小鼠差异敏感性的基因 对泰勒氏小鼠脑脊髓炎病毒(TMEV)诱导的脱髓鞘的影响 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)来说，既有临床症状的层面 以及组织病理学。这种疾病的发生是由于活跃的细胞- 介导的免疫反应，可能是迟发性超敏反应，针对 这种病毒会导致“无辜的旁观者”破坏髓鞘。 就像人类多发性硬化症一样，基因对患多发性硬化症的可能性有明显的影响。 疾病的发展，以及相关基因的鉴定/分析 可提供有关机制(包括预防或缓解)的线索 以及其他风险因素。在以下情况下，这些将特别相关 等同的人类基因是已知的，这些基因与 这些研究。 分析将沿着三条调查路线进行。第一个是 使用经典的遗传分析方法，涉及到世代和 感病与抗病杂交F1、F2代及回交后代研究 抗性菌株，以确定哪个性状是显性的，并使 对相关分离基因座数量的最小估计。后续 使用同源、重组、突变和重组近交系菌株将 帮助识别和绘制所涉及的基因座。 第二个阶段是分析抗药性动物是否不能发育。 这种疾病是因为(A)它们天生不能产生 对TMEV的破坏性免疫反应，或(2)它们是否主动 抑制潜在的反应，如果从这些抑制中释放出来 机制，会继续导致疾病。 第三个阶段是开发RFLP分析方法，用于分析 与TMEV诱导的脱髓鞘疾病相关的特异性基因和 可能的预测性用途，用于识别隔离中的哪些动物 人口中，罹患这种疾病的风险很高。

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.