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: 6534546
• 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/6534546
• 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）： 脊椎关节病是复杂的遗传性疾病，经常导致 慢性进行性关节炎和关节强直，其原因和治疗 仍然未知。HLA-1327是人类疾病的主要诱发因素， 当在大鼠中表达时，可引起类似于 人类脊椎关节病尽管我们对 HLA-B27的生理功能，这种分子在 脊椎关节病的发病机制仍然没有解决。的最新结果 我们的实验室已经表明HLA-B27具有错误折叠的异常倾向。 这种特性取决于HLA-1327的结构特征， 将其与其他HLA I类等位基因区分开来，但与 几种HLA-1327亚型的致关节炎性。蛋白质错误折叠 显著的生物学效应，特别是可以引起内质网 内质网（ER）应激反应，激活几种ER到核的信号传导 途径。这导致基因表达的许多改变，在某些情况下， 细胞包括诱导促炎细胞因子。我们已经开发出一种 一个新的假设，考虑到几个观察，从人类 研究和动物模型，HLA-1327错误折叠是潜在的基础 它的关节炎性。本提案旨在检验这一假设， 建立了转基因大鼠模型体系。具体而言，在目标I中，我们将测试 是否已经诱导了非疾病相关的HLA I类分子， 突变引起的错误折叠可产生自发性炎症性疾病的表型 对大鼠同时，我们将改变HLA-B27的肽结合特异性， 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，我们将描述基因表达的变化， HLA-B27在转基因大鼠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 提供炎症过程分子指纹的变化将 也被定义。在目标3中，我们将过表达ER的关键分子传感器 应激可以钝化ER-到-核信号传导反应，并确定 是否预防或改善HLA-1327诱导的自发性炎症反应 疾病这些实验将最终验证错误折叠假说， 提供了对自发性炎症机制的见解， 疾病的大鼠，并可能提供一种新的治疗方法， 人类脊椎关节病