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: 7462451
• 负责人: THOMAS A GRIFFIN
• 金额: $ 39.43万
• 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/7462451
• 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; Protein Overexpression; Proteins; Rattus; Reporting; Research Personnel; Risk; Role; Specificity; Stress; T-Lymphocyte; Testing; Time; Toll-like receptors; Transgenic Organisms; Up-Regulation; Work; concept; cytokine; human disease; improved; in vivo; insight; interleukin-23; link protein; macrophage; microbial; novel; 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）负责大部分对脊柱炎的遗传易感性，尤其是链氨基脊椎炎。尽管这些疾病的治疗方法有所改善，但治疗仍然不足，需要持续使用具有明确风险的药物。可以预期，对病原机制，特别是B27的作用有更好的理解会导致改善干预措施，并可能是一种预防手段。这项赠款资助的研究表明，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的B27错误折叠会导致细胞内质网（ER）的压力，这又激活了所谓的已知蛋白质反应（UPR）。初步发现表明，当通过Toll-like受体（TLR）配体刺激时，B27诱导的UPR会导致巨噬细胞强烈表达一组细胞因子。我们指的是UPR-TLR协同作用。 TLR是模式识别受体，可让细胞感知和对微生物产物反应，并且它们在连接先天和适应性免疫反应中起着重要作用。受B27诱导的UPR的细胞产生过多产生的细胞因子可能会促进慢性免疫偏差，从而导致炎症，从而将蛋白质折叠折扣与炎症性疾病联系起来。 AIM 1中提出的研究将确定B27诱导的UPR激活对包括巨噬细胞和树突状细胞在内的免疫调节细胞中产生的细胞因子的产生，并建立UPR-TLR协同的UPR成分。在AIM 2中，我们将测试UPR-TLR协同作用是否引起CD4+ T细胞的激活，并确定在炎症过程中B27-TG大鼠中是否发生这种情况。 AIM 3中的研究使用转基因方法调节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，也将使用敲低方法来确定其在疾病中的作用，因此也将针对下游细胞因子产生过度生产。这些研究将大大提高我们对HLA-B27错误折叠的理解和脊椎关节炎动物模型中的UPR。这项工作有可能推动人类转化研究，并导致针对这种病理反应的新型疗法的发展。