HLA-B27 Misfolding an the UPR in Spondyloarthritis

脊柱关节炎中的 HLA-B27 错误折叠和 UPR

• 批准号: 7650283
• 负责人: THOMAS A GRIFFIN
• 金额: $ 40.42万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-24 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7650283
• 关键词: Agonist; Alleles; Animal Model; Ankylosing spondylitis; Antigen Presentation; Antigens; Area; Arthritis; Biochemical; Biological Models; CD4 Positive T Lymphocytes; Cells; Characteristics; Chronic; Colitis; Data; Degradation Pathway; Dendritic Cells; Development; Disease; Endoplasmic Reticulum; Event; Exhibits; Feedback; Functional disorder; Funding; Gastrointestinal tract structure; Genetic Predisposition to Disease; Goals; Grant; HLA-B27 Antigen; Human; Immune; Immune response; Immune system; In Vitro; Inflammation; Inflammatory; Interferon Type I; Interleukin-17; Intervention; Investigation; Joints; Lead; Lesion; Ligands; Link; Mediating; Modeling; Molecular; Pathogenesis; Pattern recognition receptor; Pharmaceutical Preparations; Phenotype; Physiological; Play; Population; Positioning Attribute; Prevention; Production; Proteins; Rattus; Reporting; Research Personnel; Risk; Role; Specificity; Spondylarthritis; Stress; T-Lymphocyte; Testing; Time; Toll-like receptors; Transgenic Organisms; Up-Regulation; Work; cytokine; endoplasmic reticulum stress; human disease; improved; in vivo; insight; interleukin-23; link protein; macrophage; microbial; novel; overexpression; programs; protein misfolding; research study; response; reticulum cell; transcription factor; translational study

DESCRIPTION (provided by applicant): HLA-B27 (B27) is responsible for a large proportion of the genetic susceptibility to spondyloarthritis, particularly ankylosing spondylitis. Despite improvements in the treatment of these diseases, therapy remains inadequate and requires continual use of medications that carry definite risks. It is expected that a better understanding of pathogenic mechanisms, and specifically the role of B27, will lead to improved interventions and possibly a means of prevention. Studies funded by this grant have shown that B27 is a protein that misfolds. Using an animal model of spondyloarthritis, where HLA-B27 is expressed in rats (B27-Tg rats), we have shown that B27 misfolding causes stress in the endoplasmic reticulum (ER) of the cell, which in turn activates what is known as the unfolded protein response (UPR). Preliminary findings indicate that the B27-induced UPR causes macrophages to strongly overexpress a group of cytokines when stimulated by Toll-like receptor (TLR) ligands. We refer to this a UPR-TLR synergy. TLRs are pattern recognition receptors that allow cells to sense and respond to microbial products, and they play an important role in linking innate and adaptive immune responses. The cytokines overproduced by cells undergoing an B27-induced UPR may promote a chronic immune deviation resulting in inflammation, linking protein misfolding to an inflammatory disease. The studies proposed in Aim 1 will determine the effects of B27-induced UPR activation on the production of cytokines in immunoregulatory cells including macrophages and dendritic cells, and establish the UPR component of UPR-TLR synergy. In Aim 2 we will test whether UPR-TLR synergy causes activation of CD4+ T cells, and establish whether this occurs in B27-Tg rats during the development of inflammation. Studies in Aim 3 use a transgenic approach to modulate the HLA-B27-induced UPR to determine its role in inflammation. Downstream cytokines overproduced as a result of UPR-TLR synergy will also be targeted using a knockdown approach to determine their role in disease. These studies will significantly advance our understanding of HLA-B27 misfolding and the UPR in an animal model of spondyloarthritis. This work has the potential to drive translational studies in humans, and lead to the development of novel therapies targeting this pathological response.

描述（由申请人提供）：HLA-B27（B27）是脊柱关节炎，特别是强直性脊柱炎遗传易感性的主要原因。尽管这些疾病的治疗有所改进，但治疗仍然不足，需要持续使用具有明确风险的药物。预计更好地了解致病机制，特别是B27的作用，将导致改善干预措施，并可能成为预防手段。这项资助的研究表明，B27是一种错误折叠的蛋白质。使用脊椎关节炎的动物模型，其中HLA-B27在大鼠（B27-Tg大鼠）中表达，我们已经表明B27错误折叠导致细胞内质网（ER）中的应激，这反过来激活了所谓的未折叠蛋白反应（UPR）。初步研究结果表明，B27诱导的UPR导致巨噬细胞在Toll样受体（TLR）配体刺激时强烈过表达一组细胞因子。我们将此称为UPR-TLR协同作用。TLR是模式识别受体，允许细胞感知和响应微生物产物，并且它们在连接先天性和适应性免疫应答中发挥重要作用。经历B27诱导的UPR的细胞过度产生的细胞因子可能促进慢性免疫偏离，导致炎症，将蛋白质错误折叠与炎性疾病联系起来。目的1中提出的研究将确定B27诱导的UPR活化对免疫调节细胞（包括巨噬细胞和树突状细胞）中细胞因子产生的影响，并建立UPR-TLR协同作用的UPR组分。在目的2中，我们将测试UPR-TLR协同作用是否引起CD 4 + T细胞的活化，并确定这是否在炎症发展期间发生在B27-Tg大鼠中。目的3中的研究使用转基因方法来调节HLA-B27诱导的UPR以确定其在炎症中的作用。由于UPR-TLR协同作用而过度产生的下游细胞因子也将使用敲低方法靶向，以确定它们在疾病中的作用。这些研究将显著推进我们对脊椎关节炎动物模型中HLA-B27错误折叠和UPR的理解。这项工作有可能推动人类的转化研究，并导致针对这种病理反应的新型疗法的开发。