GENETIC RESISTANCE TO EAE

EAE 基因抗性

• 批准号: 6032305
• 负责人: Elizabeth P Blankenhorn
• 金额: $ 11.5万
• 依托单位: MCP HAHNEMANN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-11-11 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6032305
• 关键词: T cell receptor; animal breeding; disease /disorder model; disease /disorder proneness /risk; experimental allergic encephalomyelitis; genetic markers; genetic strain; inbreeding; laboratory rat; linkage mapping; molecular pathology; multiple sclerosis; nucleic acid sequence; phenotype

Genetic factors govern the susceptibility of individuals to a variety of human autoimmune diseases. The role of genetic factors in MS is significant. Polygenic inheritance likely characterizes MS, and it has been estimated that 1 to 3 susceptibility loci would predict the different rates of MS occurrence in studied populations. It is important to understand the nature and impact of the genes critical for susceptibility in MS, but this is problematic in any polygenic human disease, given the low general incidence, the low number of multiplex families, the small size of informative families and in the genetic diversity of the human population. Dissection of these traits in animal models is much more feasible because inbred strains may be used to control for genetic heterogeneity and even polygenic phenotypes can be understood at the genetic level. While it is not a perfect model, the genetic loci that have been found to be important in susceptibility to autoimmunity in animal models are proving useful in identifying relevant genes or pathways that are generalizable to the human conditions for which etiologic agents are unknown. We study the mechanisms and genetic control of EAE-susceptibility in inbred rats, with the goal of elucidating why certain rat strains show relatively strong resistance to the induction of this animal model of human multiple sclerosis. The ultimate goal of our research is to shed light on the genetic control autoimmunity, with possible extension to understanding the mechanisms of heritability of MS. We have now identified genetic markers that are useful for genomic screening of EAE-informative rat strain combinations and have performed the necessary preliminary genome exclusion mapping. We now propose to identify and physically map two EAE-modifying (Eaem) genes in relevant segments of rat chromosomes 4 and 5. Our results have shown that at least one gene is responsible for the EAE-susceptibility difference between F344 EAE-resistant and LEW EAE-susceptible rats; and three genes distinguish LER EAE-resistant rat from LEW rats for this trait. Our results show substantial support for the hypothesis that genes linked to the T cell receptor beta chain complex play a significant role in resistance to this autoimmune disease. In the next support period we propose to extend our genome exclusion mapping results to identify other Eae-m loci, to isolate the chromosomal segments containing these susceptibility loci in congenics, and to test the congenics for the presence of one hallmark characteristic of EAE-(MS-) susceptibility: the polarization of myelin-responsive T cells to the encephalitogenic Th1 phenotype.

遗传因素控制着个体对多种的敏感性 人自身免疫性疾病。 遗传因素在MS中的作用是 重要的。 多基因继承可能是MS的特征，并且具有 据估计，1至3个敏感性基因座将预测不同的 研究人群中MS的发生率。 重要的是 了解对易感性至关重要的基因的性质和影响 在MS中，但这在任何多基因人类疾病中都是有问题的 一般发病率低，多重家族数量少，小尺寸 信息丰富的家庭以及人类的遗传多样性 人口。 在动物模型中解剖这些特征更多 可行的，因为近交菌株可用于控制遗传 可以理解异质性，甚至是多基因表型 遗传水平。 虽然它不是一个完美的模型，但具有 发现对动物自身免疫的敏感性很重要 事实证明，模型可用于识别相关基因或途径 可以推广到病因的人类条件 未知。 我们研究了近交的EAE敏感性的机制和遗传控制 大鼠的目的是阐明为什么某些大鼠菌株相对显示 强烈抵抗这种人类倍数动物模型的诱导性 硬化。 我们研究的最终目标是阐明 遗传控制自身免疫，可能会扩展以了解 MS遗传力的机制。 我们现在已经确定了遗传标记 可用于筛查EAE信息性大鼠菌株的基因组筛查 组合并进行了必要的初步基因组排除 映射。 现在，我们建议识别和物理绘制两个EAE修改 （EAEM）在大鼠染色体4和5相关片段中的基因。我们的结果 已经表明，至少一个基因负责EAE敏感性 F344抗EAE和Lew Eae敏感的大鼠之间的差异；和 三个基因将耐抗性的大鼠与该特征的lew大鼠区分开。 我们的结果表明了基因相关的假设的大量支持 到T细胞受体Beta链链复合物在 对这种自身免疫性疾病的抵抗力。 在下一个支持期内 建议扩展我们的基因组排除映射结果以识别其他 eae-m loci，以分离包含这些的染色体片段 敏感性的易感位点，并测试磁性的 EAE（MS-）敏感性的一个标志性特征的存在： 髓磷脂反应性T细胞对脑源性Th1的极化 表型。