Identification of genes regulating arthritis in rats.

描述（由申请人提供）：大鼠胶原诱导关节炎（CIA）和蛋白酶诱导关节炎（PIA）是成熟的实验动物模型，已被用于深入了解类风湿关节炎（RA）的发病机制，类风湿关节炎是一种在大多数人群中患病率为1%的慢性致残性疾病。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%，但对这些基因知之甚少。该建议的基本假设是，控制大鼠CIA和PIA易感性和严重程度的非mhc位点将与了解RA的发病机制高度相关，并可能为开发更特异性的治疗方法提供新的靶点，以及用于诊断和预后的新的生物标志物。在本研究提出之前的实验中，对MHC相同的关节炎易感性DA和抗关节炎的ACI自交系大鼠进行F2交叉的全基因组筛选，发现了3个非MHC数量性状位点（QTL） Cia7、C/a70和C/a27分别位于染色体2、2和10上。基因型引导qtl同源菌株的产生。哒。与DA相比，ACI（CialO）大鼠的关节炎形式明显较轻，通常没有滑膜增生或滑膜形成，并且关节结构保留。Cia27区间从DA到ACI的转换。DA（Cia27）基因足以使这些大鼠对CIA易感。因此，我们假设CIA和PIA的健壮和高渗透性表型取决于Cia7、C/a70和Cia27的易感等位基因的存在。此外，Cia7、C/a70和C/a27位于含有调节不同形式自身免疫性疾病（包括RA）的位点的区域，这表明这些大鼠基因可能与人类疾病有关。这一建议旨在识别和表征这些基因。在Aim 1中，含有关节炎基因的关键区域将在重组亚基因中逐渐减少到< 1mb。与关节炎相关的亚表型将继续被识别，并将在基因中进行研究，以获得基因功能和身份的早期线索。在Aim 2中，将对C/a70和C/a27关键区域内的候选基因进行测序和分析，以寻找区分DA和ACI的致病多态性/突变。鉴定的基因和等位基因将在体外和体内研究中进行功能表征。

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 as new biomarkers for diagnosis and prognosis. In experiments leading up to the present proposal, a genome-wide screen done in an F2 intercross between the MHC identical arthritis- susceptible DA and the arthritis-resistant ACI inbred rat strains studied for CIA identified three non-MHC quantitative trait loci (QTL) Cia7, C/a70and C/a27on chromosomes 2, 2, and 10, respectively. Genotype- guided QTL-congenic strains were generated. DA.ACI(CialO) rats developed a significantly milder form of arthritis, typically with no synovial hyperplasia or pannus formation, and preservation of the joint architecture, compared with DA. The transfer of the Cia27 interval from DA into ACI.DA(Cia27) congenics, was enough to render these rats susceptible to CIA. Thus, it is hypothesized that the robust and highly penetrant phenotype of CIA and PIA depends on the presence of susceptibility alleles at Cia7, C/a70and Cia27. Additionally, Cia7, C/a70and C/a27are located in regions syntenic to those containing loci regulating different forms of autoimmune diseases, including RA, suggesting that these rat genes will be relevant to human disease. This proposal aims at identifying and characterizing those genes. In Aim 1 the critical regions containing the arthritis genes will be progressively reduced to <1 Mb in recombinant subcongenics. Sub-phenotypes relevant to arthritis will continue to be identified and will be studied in congenics to obtain early clues to gene function and identity. In Aim 2 candidate genes within the critical regions of C/a70and C/a27will be sequenced and analyzed for disease-causing polymorphisms/mutations that differentiate DA from ACI. The identified genes and alleles will be functionally characterized in in vitro and in vivo studies.