Identification of susceptibility gene(s) controlling autoantibody production in collagen induced arthritis

Agen诱导的小鼠关节炎(CIA)是应用最广泛的自身免疫实验模型之一，具有许多与类风湿关节炎(RA)相似的特征。与RA一样，CIA的易感性受许多相互作用的基因控制。我们和其他人估计有40多个数量性状基因座(QTL)控制着CIA发病的不同方面。在最近的一项研究中，我们在(FVB/N和DBA/1J)F2代中进行了基因组扫描，以确定新的CIA-QTL，并在5号染色体上发现了一个新的QTL Cia27，它控制着IgG2a抗II型胶原抗体和疾病的易感性。随后，我们使用先进的交叉线将该基因定位到4.1Mb区域，该区域仅包含39个基因。在这项建议中，我们的目标是确定Cia27的易感基因。为了实现这一目标，将进行一系列经典的和新颖的基因定位策略和功能分析。此外，这一新的易感基因控制的疾病途径也将被研究。

agen-induced arthritis (CIA) in the mouse is one of the most widely used autoimmune experimental models with many features similar to rheumatoid arthritis (RA). Like RA, the susceptibility to CIA is controlled by many interacting genes. We and others estimate that more than 40 Quantitiave Trait Loci (QTL), control different aspects of CIA pathogenesis. In a recent study we conduced a genome scan in in (FVB/N and DBA/1J) F2 progeny to identify novel CIA-QTLs and identified Cia27, a novel QTL on chromosome 5, controlling IgG2a anti collagen II antibody and disease susceptibility. We subsequently refined this locus using an advanced intercross line down to a 4.1 Mb region, containing only 39 genes. In this proposal we aim to identify the susceptibility gene for Cia27. To achieve this goal, a series classical and novel gene-mapping strategies and functional assays will be performed. Furthermore, the disease pathway controlled by this novel susceptibility gene will be investigated.