GENETIC RESISTANCE TO EAE

本提案中的研究将确定 基因负责易感性和抵抗实验 过敏性脑脊髓炎，人类疾病的动物模型， 多发性硬化 实验性过敏性脑脊髓炎（EAE）可以是 在LEW大鼠品系中诱导，但基因不同 LEW抗性（LER）和Brown Norway（BN）近交系完全分离。 抗EAE诱导。 我们在这个系统中对回交鼠的研究 使我们得出结论，三个遗传位点决定了 这些大鼠EAE，这三个决定的严重程度之一， 临床症状。 我们的目标是找到并鉴定这些基因。 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， 帮助我们缩小对三个EAE修饰基因的搜索范围 基因组筛选方法（如微卫星定位）是强大的 用于绘制可遗传疾病修饰基因座的工具。 一个成功的映射 实验允许研究人员排除大部分的 基因组与所研究的性状无关，并缩小了 后续实验的重点是基因组间隔， 含有感兴趣的基因。 基因组筛选在动物中的应用 几种疾病状态（例如，糖尿病，高血压， 和癫痫）已经导致多个疾病修饰基因座的定位。 这种类型的筛选具有进一步的潜力， 最终克隆这些基因。 两者之间的相当大的同源性 大鼠和人类基因组的组织以及EAE之间的相似性 和人类脱髓鞘疾病的研究， 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。 所有这些特性使得 应用大规模基因组方法从我们广泛的样本， 收集的回交大鼠分离EAE性状的理想 为了实现我们的目标。

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.