Identification of arthritis genes in DAxF344 congenic rats.

DAxF344 同类大鼠关节炎基因的鉴定。

• 批准号: 7126533
• 负责人: Percio S Gulko
• 金额: $ 35.45万
• 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/7126533
• 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(申请人提供)：胶原诱导的关节炎(CIA)和Pristane诱导的大鼠关节炎(PIA)是公认的实验动物模型，已被用于深入了解类风湿性关节炎(RA)的发病机制，类风湿性关节炎(RA)是一种慢性和常见的致残性疾病，在大多数人群中的患病率为1%。CIA、PIA和RA是受MHC基因和非MHC基因调控的复杂性状疾病。非MHC基因占类风湿关节炎遗传贡献的50%-75%，但对这些基因知之甚少。这一建议的基本假设是，控制大鼠对CIA和PIA的易感性和严重性的非MHC基因座将与理解RA的发病机制高度相关，并可能为开发更特异的治疗方法创造新的靶点，以及为诊断和预后提供新的工具。在导致本建议的实验中，在MHC不协调的近亲交配的关节炎易感DA和抗关节炎的F344大鼠品系之间的F2杂交中进行的全基因组筛查发现，三个非MHC数量性状基因座(QTL)Cia3、Cia5和Cia6分别位于第4、10和8号染色体上。这些QTL的关节炎调节作用在基因引导的同源基因株中得到证实，其中F344派生的间隔被引入DA背景。这些QTL同源菌株受到保护，并发展为一种明显较轻的关节炎。根据以前的研究，假设CIA和PIA的强健和高渗透性表型依赖于Cia3、Cia5和Cia6的易感等位基因的存在。此外，Cia3和Cia5位于与包含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。这项提议旨在识别和描述这些基因。在目标1上，将完成亚基因菌株的构建，以将包含关节炎基因的关键区域减少到1Mb。与关节炎相关的亚型将在遗传学中进行鉴定和研究，以获得基因功能和身份的早期线索。在AIM上，将对关键区域内的2个候选基因进行测序和分析，以寻找区分DA和F344的致病多态/突变。已确定的基因和疾病变异体将在体外和体内研究中进行功能表征。