MOLECULAR AND GENETIC STUDIES OF EAE IN COISOGENIC RATS

这项研究计划旨在阐明遗传影响。 关于动物对实验诱导的敏感性 自身免疫性脑脊髓炎(EAE)。老鼠EAE是最好的之一 人类疾病的模型，多发性硬化症。在大鼠和 男人，这些疾病是由T淋巴细胞介导的，T淋巴细胞逃逸 从自我容忍的正常约束中解脱出来，并对 中枢神经系统的组成部分，称为基本髓鞘 蛋白。在这两个物种中，主要组织相容性复合体(MHC) 基因有助于个体对疾病的易感性； 然而，已知的是，其他背景基因也在 重要的角色。背景基因的同一性 影响目前是密集调查的主题。 研究基因(除MHC基因外)的极佳模型 支配中枢神经系统自身免疫的是Lewis/Lewis抵抗(LER) 老鼠组合。不敏感的LER大鼠实际上是共同的 与高度易感的Lewis大鼠同源，但它们共享 相同(易感)MHC单倍型。我们的初步证据 表明T细胞受体β链基因座是从根本上 两个菌株之间的差异，因此我们认为T 细胞受体基因复合体对分化有重要影响 这两个菌株对EAE的敏感性。我们的研究有 有可能为那些鲜为人知的人提供理由 多发性硬化症的遗传性，并提供进一步的见解 探讨该病的发病机制。

This research proposal is designed to elucidate genetic influences on the susceptibility of animals to experimentally induced autoimmune encephalomyelitis (EAE). Rat EAE is one of the best models for the human illness, multiple sclerosis. In both rats and man, these diseases are mediated by T lymphocytes, which escape from the normal constraints of self-tolerance and respond to a component of the central nervous system called myelin basic protein. In both species, major histocompatibility complex (MHC) genes contribute to the susceptibility of individuals for disease; however, it is known that other background genes also play a significant role. The identity of the background genetic influences is currently the subject of intense investigation. An excellent model in which to study genes (other than MHC loci) that govern CNS autoimmunity is the Lewis/Lewis-resistant (LER) rat combination. The non-susceptible LER rat is virtually co- isogenic with the highly susceptible Lewis rat, yet they share the same (susceptible) MHC haplotype. Our preliminary evidence shows that the T cell receptor beta chain loci are radically different between the two strains, and thus we propose that the T cell receptor gene complex has a major effect on the differential EAE-susceptibility of these two strains. Our studies have the potential to provide a rationale for the poorly understood heritability of multiple sclerosis, and to provide further insight into the mechanism of pathogenesis of this disease.