HLA-B27 Misfolding in Spondyloarthropathy Pathogenesis

脊柱关节病发病机制中的 HLA-B27 错误折叠

• 批准号: 6437975
• 负责人: ROBERT A. COLBERT
• 金额: $ 36.86万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-28 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6437975
• 关键词: MHC class I antigen; arthritis; disease /disorder model; endoplasmic reticulum; gene expression; genetically modified animals; inflammation; laboratory rat; microarray technology; model design /development; molecular pathology; protein binding; protein folding; spondylitis

DESCRIPTION (provided by applicant): Spondyloarthropathies are complex genetic diseases that frequently result in chronic, progressive arthritis and ankylosis, and for which the cause and cure remain unknown. HLA-1327 is a major predisposing factor in human disease, and when expressed in rats can cause a spontaneous inflammatory disease resembling human spondyloarthropathies. Despite considerable knowledge about the physiological function of HLA-B27, the role of this molecule in the pathogenesis of spondyloarthropathies remains unresolved. Recent results from our laboratory have shown that HLA-B27 has an abnormal tendency to misfold. This characteristic is dependent on structural features of HLA-1327 that distinguish it from other HLA class I alleles, yet correlate strongly with the arthritogenicity of several HLA-1327 subtypes. Protein misfolding has significant biological effects, and in particular can cause an endoplasmic reticulum (ER) stress response that activates several ER-to-nucleus signaling pathways. This results in many alterations in gene expression, which in some cells includes the induction of pro-inflammatory cytokines. We have developed a novel hypothesis that takes into account several observations from human studies and animal models, that HLA-1327 misfolding is the underlying basis for its arthritogenicity. This proposal is designed to test this hypothesis using an established transgenic rat model system. Specifically, in Aim I we will test whether a non-disease associated HLA class I molecule that has been induced to misfold by mutation can produce a phenocopy of spontaneous inflammatory disease in rats. In parallel we will alter the peptide binding specificity of HLA-B27 without correcting misfolding, and determine whether it still causes disease. In Aim 2 we will characterize changes in gene expression that result from HLA-B27 misfolding in cells and tissues from transgenic rats prior to the development of any clinical disease, using gene expression microarrays. Later changes that provide a molecular fingerprint of the inflammatory process will also be defined. In Aim 3 we will overexpress a key molecular sensor of ER stress that can blunt the ER-to-nuclear signaling response, and determine whether it prevents or ameliorates HLA-1327 induced spontaneous inflammatory disease. These experiments will definitively test the misfolding hypothesis, provide insights into the mechanisms responsible for spontaneous inflammatory disease in rats, and may provide the basis for a novel therapeutic approach to human spondyloarthropathies.

描述(由申请人提供)： 脊柱关节病是一种复杂的遗传性疾病，经常导致 慢性进行性关节炎和强直，其病因和治疗 仍然不为人所知。人类白细胞抗原-1327是人类疾病的主要诱因， 在大鼠体内表达时会导致一种类似于 人类脊椎关节病。尽管有相当多的关于 人类白细胞抗原-B27的生理功能，该分子在人类免疫缺陷中的作用 脊椎关节病的发病机制仍未解决。最近的结果来自 我们实验室发现，人类白细胞抗原B27有错误折叠的异常倾向。 这一特性依赖于人类白细胞抗原-1327的结构特征 将其与其他HLAI类等位基因区分开来，但与 几种人类白细胞抗原-1327亚型的致关节炎作用。蛋白质的错误折叠有 显著的生物效应，特别是可以引起内质 激活多个内质网到细胞核信号的网状(ER)应激反应 小路。这导致了基因表达的许多变化，在某些情况下 细胞包括促炎细胞因子的诱导。我们已经开发出一种 考虑到人类的几个观察结果的新假说 研究和动物模型表明，人类白细胞抗原-1327的错误折叠是 它的致关节炎作用。该提案旨在使用以下工具来检验这一假设 建立转基因大鼠模型体系。具体地说，我们将在AIM I中测试 非疾病相关的人类白细胞抗原I类分子是否已被诱导为 突变导致的错误折叠可产生自发性炎症性疾病的表型 在老鼠身上。同时，我们将改变人类白细胞抗原-B27的多肽结合特异性 而不纠正错误折叠，并确定它是否仍然会导致疾病。 在目标2中，我们将描述由以下因素引起的基因表达变化 转基因大鼠体内HL A-B27在细胞和组织中的错误折叠 任何临床疾病的发展，使用基因表达微阵列。后来 提供炎症过程的分子指纹的变化将 也被定义为。在目标3中，我们将过度表达内质网的一个关键分子传感器 可以钝化内质网到核的信号反应的压力，并决定 预防或改善人类白细胞抗原-1327诱导的自发性炎症 疾病。这些实验将明确地检验错误折叠假说， 提供对自发性炎症的机制的见解 疾病，并可能为新的治疗方法提供基础。 人类脊椎关节病。