GENETIC RESISTANCE TO EAE

EAE 基因抗性

• 批准号: 2265563
• 负责人: Elizabeth P Blankenhorn
• 金额: $ 16.18万
• 依托单位: ALLEGHENY UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2265563
• 关键词: T cell receptor; disease /disorder model; experimental allergic encephalomyelitis; genetic mapping; genetic markers; genetic strain; laboratory rat; molecular pathology; multiple sclerosis; nucleic acid sequence; polymerase chain reaction

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.

该提案中的研究将确定 负责敏感性和对实验性抗性的基因 过敏性脑脊髓炎是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）可以是 在Lew大鼠菌株中诱导，但遗传学不同 抗耐药（LER）和棕色挪威（BN）的近交菌株完全是 对EAE感应的抗性。 我们在该系统中与反向交叉大鼠的工作 导致我们得出结论，三个遗传基因座管理易感性 这些老鼠是伊斯的，这三个决定了 临床症状。 我们的目标是找到和识别这些基因。 进行了搜索可能的候选基因以解释这一点 继承模式，我们已将基因组筛查技术转向 帮助我们缩小搜索三个EAE修改基因的搜索。 基因组筛选方法（例如微卫星映射）是强大的 映射可遗传疾病改良基因座的工具。 成功的映射 实验允许研究人员排除大部分 与正在研究的特征无关的基因组，并缩小 随后的实验重点是可能的基因组间隔 包含感兴趣的基因。 在动物中使用基因组筛查 几种疾病状态的模型（例如，糖尿病，高血压， 癫痫病）导致了多种疾病改良基因座的位置。 这种类型的筛选具有允许的进一步潜力 这种基因的最终克隆。 在 大鼠和人类基因组的组织以及EAE之间的相似之处 人类脱髓鞘疾病对 假设基因在大鼠EAE中很重要将很重要 在多发性硬化症中。 所有这些功能使 将大规模基因组方法应用于我们广泛的样品 收集回杂交大鼠的EAE特质是理想的 结合实现我们的目标。