Arthritis genes in DAxF344 congenic rats

DAxF344 同类大鼠的关节炎基因

• 批准号: 7032732
• 负责人: Percio S Gulko
• 金额: $ 35.96万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-22 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7032732
• 关键词: animal breeding; cellular pathology; disease /disorder model; gene mutation; genetic polymorphism; genetic screening; genetic strain; genetic susceptibility; laboratory rat; nucleic acid sequence; rheumatoid arthritis

DESCRIPTION (provided by applicant): Collagen-induced arthritis (CIA) and pristane-induced arthritis (PIA) in rats are well-established experimental animal models that have been used to gain insight into the pathogenesis of rheumatoid arthritis (RA), a chronic and commonly disabling disease with a prevalence of 1% in most populations. CIA, PIA and RA are complex trait diseases regulated by MHC and non-MHC genes. Non-MHC genes account for 50-75% of the genetic contribution to RA, yet, little is known about those genes. The underlying hypotheses of this proposal are that the non-MHC loci governing susceptibility to and severity of CIA and PIA in rats will be highly relevant to understanding the pathogenesis of RA and could generate new targets for the development of more specific therapies, as well new tools for diagnosis and prognosis. In experiments leading up to the present proposal, a genome-wide screen done in a F2 intercross between the MHC discordant inbred arthritis-susceptible DA and the arthritis-resistant F344 rat strains identified three non-MHC quantitative trait loci (QTL) Cia3, Cia5 and Cia6 on chromosomes 4, 10 and 8, respectively. The arthritis-regulatory effect of these QTLs was confirmed in genotype-guided congenic strains where the F344-derived interval was introgressed into the DA background. These QTL-congenic strains were protected and developed a significantly milder form of arthritis. Based on these prior studies, it is hypothesized that the robust and highly penetrant phenotype of CIA and PIA depends on the presence of susceptibility alleles at Cia3, Cia5 and Cia6. Additionally, Cia3 and Cia5 are located in regions homologous to those containing RA susceptibility genes, suggesting that the same genes might regulate arthritis on both species. This proposal aims at identifying and characterizing those genes. On aim 1 the construction of subcongenic strains will be completed in order to reduce the critical regions containing the arthritis genes to <1Mb. Subphenotypes relevant to arthritis will be identified and studied in congenics to obtain early clues to gene function and identity. On aim 2 candidate genes within the critical regions will be sequenced and analyzed for disease-causing polymorphisms/mutations that differentiate DA from F344. The identified genes and disease variants will be functionally characterized in in vitro and in vivo studies.

描述（由申请方提供）：大鼠中胶原诱导的关节炎（CIA）和降植烷诱导的关节炎（PIA）是已充分建立的实验动物模型，已用于深入了解类风湿性关节炎（RA）的发病机制，RA是一种慢性和常见致残性疾病，在大多数人群中的患病率为1%。CIA、PIA和RA是由MHC和非MHC基因调控的复杂性状疾病。非MHC基因占RA遗传贡献的50-75%，然而，对这些基因的了解甚少。这一建议的基本假设是，非MHC基因座管理的敏感性和严重程度的CIA和PIA的大鼠将是高度相关的了解RA的发病机制，并可能产生新的目标，为发展更具体的治疗，以及新的工具，诊断和预后。在导致本提案的实验中，在MHC不一致的近交系关节炎易感DA和关节炎抗性F344大鼠品系之间的F2互交中进行的全基因组筛选分别在染色体4、10和8上鉴定出三个非MHC数量性状位点（QTL）Cia 3、Cia 5和Cia 6。这些QTL的关节炎调控效应在基因型引导的同源株系中得到证实，其中F344衍生的间隔渗入DA背景中。这些QTL同源菌株受到保护，并发展出一种明显较轻的关节炎形式。基于这些先前的研究，假设CIA和PIA的稳健和高度外显表型取决于Cia 3、Cia 5和Cia 6处的易感性等位基因的存在。此外，Cia 3和Cia 5位于与含有RA易感基因的区域同源的区域，这表明相同的基因可能调节两个物种的关节炎。该提案旨在识别和表征这些基因。根据目标1，将完成亚同源菌株的构建，以将含有关节炎基因的关键区域减少至<1 Mb。关节炎相关的亚表型将被确定和研究的同类基因，以获得早期线索的基因功能和身份。根据目标2，将对关键区域内的候选基因进行测序，并分析区分DA和F344的致病多态性/突变。将在体外和体内研究中对鉴定的基因和疾病变体进行功能表征。