Analyzing Disease Mechanisms in a Mouse Model of Spondyloarthritis

 描述(申请人提供)：脊椎炎包括一组炎症性疾病，具有共同的遗传风险因素和重叠的临床特征。来自全基因组关联研究的数据表明，IL-23在脊柱性关节炎发病机制中起着核心作用。最近的一份报告(Sherlock等人)Natural Medicine 2012)描述了一种由IL-23在成年动物中过表达导致的小鼠脊柱性关节炎样疾病，并确定了一种CD4-CD8双阴性T细胞亚群，该亚群通过分泌IL-17A和IL-22来应对IL-23而介导疾病的发展。该项目是建立在IL-23小环诱导的脊柱性关节炎模型在阐明脊柱性关节炎发病机制方面具有巨大潜力的前提下的。具体目的1分析控制疾病介导性IL-23受体阳性的糖尿病肾病T细胞发育和功能的因素。利用一组基因敲除的小鼠，我们将检验这些细胞是MHC-I类限制性HLATCR阳性细胞的假设，这可能代表了αβ-B27疾病关联、IL-23和脊柱性关节炎的发展之间的联系。我们将进一步探索转录的功能 这些细胞中的T-bet和Ahr因子。在特定的目标2中，我们开始询问下游介体IL-22诱导骨增殖的机制，并确定候选途径，以便将来进行更详细的分析。

 DESCRIPTION (provided by applicant): Spondyloarthritis encompasses a group of inflammatory disorders with shared genetic risk factors and overlapping clinical features. Data from genome-wide association studies point toward a central role for IL-23 in spondyloarthritis pathogenesis. A recent report (Sherlock et al. Nature Medicine 2012) described a spondyloarthritis-like illness in mice induced by IL-23 overexpression in adult animals and identified a CD4-CD8- double negative T cell subset that mediated disease development by secreting IL-17A and IL- 22 in response to IL-23. The proposed project is built on the premise that the IL-23 minicircle-induced spondyloarthritis model has enormous potential for elucidating the pathogenesis of spondyloarthritis. Specific Aim 1 analyzes factors controlling the development and function of the disease-mediating IL-23 receptor positive DN T cells. Using a panel of knockout mice we will test the hypothesis that these cells are MHC class I restricted αβTCR positive cells that may represent a link between HLA-B27 disease association, IL-23 and the development of spondyloarthritis. We will further explore the function of the transcription factors T-bet and Ahr in these cells. In Specific Aim 2 we begin to interrogate the mechanism of osteoproliferation induced by the downstream mediator IL-22 and identify candidate pathways for future more detailed analysis.