GENETIC RESISTANCE TO EAE

这项提案中的研究将确定 与实验性肺炎易感性和抗药性有关的基因 过敏性脑脊髓炎，人类疾病的动物模型， 多发性硬化症。实验性过敏性脑脊髓炎(EAE)可 在卢大鼠品系中诱导，但遗传上不同 抗Lew(LER)和棕色挪威(BN)近交系完全 抗EAE诱导。我们在这个系统中用回交鼠做的工作 使我们得出结论，有三个遗传位点控制着易感性 这三种动物中的一种决定了EAE的严重程度 临床症状。我们的目标是找到并识别这些基因。 在对可能的候选基因进行搜索以解释这一点之后 遗传模式，我们已经转向基因组筛选技术来 帮助我们缩小对三个修改EAE基因的搜索范围。 基因组筛选方法(如微卫星图谱)是强有力的 绘制可遗传疾病修饰基因的工具。一张成功的地图 实验允许调查者排除很大一部分 与研究中的性状没有关联的基因组，并缩小了 后续实验的重点是基因组间隔，很可能 含有感兴趣的基因。基因组筛选技术在动物中的应用 多种疾病状态的模型(例如，糖尿病、高血压、 和癫痫)导致了多个疾病修饰基因的位置。 这种类型的筛查具有进一步的潜力，允许 最终克隆这样的基因。它们之间的相当大的同源性 大鼠和人类基因组的组织及其与EAE的相似性 而人类脱髓鞘疾病给了人们相当大的信任 假设在大鼠EAE中发现的重要基因将是重要的 多发性硬化症也是如此。所有这些功能都使 大规模基因组学方法在我国广泛采集的样本中的应用 收集分离EAE性状的回交鼠是一种理想的选择 为了达到我们的目标而进行的联合。

Studies in this proposal will determine the location and identity of genes responsible for susceptibility and resistance to experimental allergic encephalomyelitis, an animal model for the human disorder, multiple sclerosis. Experimental allergic encephalomyelitis (EAE) can be induced in the LEW rat strain, but the genetically dissimilar LEW-resistant (LER) and Brown Norway (BN) inbred strains are completely resistant to EAE induction. Our work with backcross rats in this system has led us to conclude that three genetic loci govern the susceptibility of these rats to EAE, and that one of these three determines severity of clinical symptoms. Our objective is to find and identify these genes. After conducting a search of likely candidate genes to explain this inheritance pattern, we have turned to genomic screening technology to help us narrow our search for the three EAE-modifying genes. Genomic screening methods (such as microsatellite mapping) are powerful tools for mapping heritable disease-modifying loci. A successful mapping experiment allows the investigator to exclude large portions of the genome that are not linked to the trait under study, and narrows the focus of subsequent experiments to genomic intervals that are likely to contain a gene of interest. The use of genomic screening in animal models of several disease states (for example, diabetes, hypertension, and epilepsy) has led to the location of multiple disease-modifying loci. This type of screening has the further potential for allowing the eventual cloning of such genes. The considerable homology between the organization of rat and human genomes and the similarities between EAE and the human demyelinating disease lend considerable credence to the hypothesis that genes found to be important in rat EAE will be important in multiple sclerosis as well. All of these features make the application of large-scale genomic methods to samples from our extensive collection of backcross rats segregating for the EAE trait an ideal combination for meeting our goal.