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: 6794579
• 负责人: ROBERT A. COLBERT
• 金额: $ 37万
• 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/6794579
• 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.

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