MOLECULAR AND GENETIC STUDIES OF EAE IN COISOGENIC RATS

这项研究计划旨在阐明遗传影响 动物对实验诱导的 自身免疫性脑脊髓炎（EAE）。 老鼠EAE是最好的之一 人类疾病多发性硬化症的模型。 大鼠和 这些疾病是由T淋巴细胞介导的， 从自我宽容的正常约束，并回应一个 中枢神经系统的一种成分，称为髓鞘碱 蛋白 在这两个物种中，主要组织相容性复合体（MHC） 基因导致个体对疾病的易感性; 然而，已知其他背景基因也发挥作用， 重要的角色。 背景基因的身份 影响是目前深入调查的主题。 一个研究基因（MHC基因座除外）的极好模型 控制CNS自身免疫的是刘易斯/路易斯抗性（LER） 大鼠组合。 非易感LER大鼠实际上是共- 与高度易感的刘易斯大鼠同基因，但它们共享 相同（易感）MHC单倍型。 我们的初步证据 显示T细胞受体β链位点从根本上 两种菌株之间的差异，因此我们建议，T 细胞受体基因复合体对分化有主要影响， 这两种菌株的EAE敏感性。 我们的研究 有可能为人们所知甚少的 多发性硬化症的遗传性，并提供进一步的见解 这种疾病的发病机制。

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.