GENETICS OF ARTHRITIS IN MRL/1PR MICE AND IN HUMAN RHEUMATOID ARTHRITIS

MRL/1PR 小鼠和人类类风湿性关节炎的关节炎遗传学

• 批准号: 3728066
• 负责人: MICHAEL F SELDIN
• 金额: --
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3728066
• 关键词: antiantibody; biomarker; computer assisted sequence analysis; enzyme linked immunosorbent assay; family genetics; gene expression; genetic mapping; genetic polymorphism; genotype; histocompatibility gene; histocompatibility typing; human genetic material tag; human subject; laboratory mouse; nucleic acid sequence; pathologic process; phenotype; polymerase chain reaction; pulsed field gel electrophoresis; restriction fragment length polymorphism; rheumatoid arthritis; rheumatoid factor; serology /serodiagnosis; southern blotting; synovitis

The MRL/MpJ-lpr (MRL-lpr) mouse develops spontaneous inflammatory Genes from the MRL strain are necessary for this synovitis since lpr since lpr congenics, including C57BL/6J-lpr (B6-lpr), AKR/J-lpr and not manifest arthritis. Preliminary studies using F1 crosses between MRL- crosses between MRL-lpr and B6-lpr mice indicate that the inheritance of semidominant. In order to identify the number of genes, the chromosomal chromosomal location of the arthritis susceptibility gene(s) and determine relationship between synovitis and functional and serologic abnormalities, abnormalities, we will analyze backcross and/or F2 intercrosses utilizing BL/6-lpr parental strains. The histology of the hind limb knees of these knees of these mice will be scored and the results correlated with rheumatoid factor, anti-DNA antibodies, and Ig levels including IgG3. DNA including lgG3. DNA from each of the progeny will be examined for throughout the mouse genome at approximately 15 centi-Morgan intervals. Morgan intervals. Microsatellite polymorphisms that are detected by and restriction fragment length variants will be used to accurately define used to accurately define haplotypes. The segregation of loci that affect determined using computer programs that are designed to analyze complex analyze complex genetic diseases. Since the mouse and human genomes are multiple chromosome segments that have been conserved over evolution, these evolution, these studies have the potential to identify putative genetic the inheritance and pathogenesis of human inflammatory arthropathies. arthropathies. Therefore the proposed studies may suggest candidate genes critical to the development of disease in both mice and humans. As part of As part of this effort, human families with rheumatoid arthritis will also to determine whether disease segregates with candidate loci including those including those suggested by the MRL study. We will use an affected that does not presuppose a mode of inheritance. The proposed studies have proposed studies have the potential to identify non-major important in the pathogenesis of inflammatory arthropathy. inflammatory arthropathy.

MRL/MpJ-lpr（MRL-lpr）小鼠发生自发性炎症反应， 来自MRL菌株的基因是这种滑膜炎所必需的，因为lpr 由于lpr同源，包括C57 BL/6 J-lpr（B6-lpr）、AKR/J-lpr和 没有明显的关节炎 使用MRL-1之间的F1杂交的初步研究 MRL-lpr和B6-lpr小鼠之间的杂交表明， 半显性的 为了确定基因的数量，染色体 关节炎易感基因的染色体定位，并确定 滑膜炎与功能和血清学异常之间的关系， 异常，我们将分析回交和/或F2杂交利用 BL/6-lpr亲本菌株。 这些动物后肢膝关节的组织学 将对这些小鼠的膝关节进行评分，并将结果与 类风湿因子、抗DNA抗体和包括IgG 3的IG水平。 DNA 包括IgG 3。 每一个后代的DNA将被检查， 在小鼠基因组中以大约15厘摩的间隔。 摩根间隔。 微卫星多态性检测 和限制性片段长度变体将用于准确地定义 用于精确定义单倍型。 基因座的分离 使用计算机程序来确定，该计算机程序被设计用于分析复杂的 分析复杂的遗传疾病。 因为老鼠和人类的基因组 在进化过程中保守的多个染色体片段， 进化，这些研究有可能确定假定的遗传 人类炎性关节病的遗传和发病机制。 关节病 因此，拟议的研究可能会提出候选基因， 对小鼠和人类疾病的发展至关重要。 的一部分 作为这一努力的一部分，患有类风湿性关节炎的人类家庭也将 为了确定疾病是否与候选基因座分离， 包括最大残留限量研究所提出的建议。 我们将使用受影响的 并不以继承方式为前提。 拟议的研究有 拟议的研究有可能确定非重大的 在炎症性关节病的发病机制中很重要。 炎性关节病。