The Role of DEK in the Development of Arthritis

DEK 在关节炎发展中的作用

• 批准号: 8088226
• 负责人: Nirit Mor-Vaknin
• 金额: $ 10.98万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8088226
• 关键词: Acute Myelocytic Leukemia; Adolescent; Adult; Adverse effects; Affect; Age; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigen-Antibody Complex; Area; Arthritis; Autoantigens; Autoimmune Diseases; Biological Assay; Blood; CD8-Positive T-Lymphocytes; Cell Lineage; Cells; Chemotactic Factors; Chemotaxis; Child; Child health care; Childhood; Chromatin; Chronic Childhood Arthritis; Clinical; Co-Immunoprecipitations; Cyclosporine; Cyclosporins; Cytoplasm; DEK gene; DNA biosynthesis; Data; Deformity; Development; Dexamethasone; Diagnosis; Disease; Experimental Models; Extracellular Space; Eye; Flare; Future; Gene Expression Regulation; Genes; Genetic Polymorphism; Goals; Granulomatous; Human; IL8 gene; IL8RA gene; IL8RB gene; Immune; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory; Joints; Knowledge; Lead; Learning; Link; Measures; Messenger RNA; Migration Assay; Modeling; Molecular; Natural Killer Cells; Nuclear; Nuclear Protein; Oncogenes; Organ; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphoproteins; Play; Process; Proteins; Publishing; Reaction; Recombinants; Recruitment Activity; Reporting; Research Personnel; Rheumatoid Arthritis; Risk; Role; Sarcoidosis; Scleroderma; Serum; Severities; Structure; Synovial Fluid; Synovial Membrane; Systemic Lupus Erythematosus; Testing; Therapeutic Intervention; Transcriptional Regulation; Uveitis; Vesicle; autoimmune arthritis; base; casein kinase II; chemokine receptor; design; disability; disorder control; early childhood; human Dek protein; immune activation; improved; in vivo; inhibitor/antagonist; insight; loss of function; macrophage; monocyte; neoplastic cell; neutrophil; novel; prevent; receptor; receptor binding

DESCRIPTION (provided by applicant): Juvenile rheumatoid (or idiopathic) arthritis (JRA/JIA) is the most common cause of childhood disability. Even the mildest form of the disease carries a significant risk of joint deformation and loss of function that foreshadows lifelong discomfort and disability. The disease affects 1child in every 200 under the age of 16. Controlling the disease in early childhood is important to prevent the deformity and later disability in children with JRA/JIA. However, the current treatment paradigm mandating earlier use of aggressive, anti- inflammatory drugs has potential harmful side effects making it imperative that we develop measures that can detect impending disease flares and develop better drugs for treatment with fewer side effects. In order to achieve these goals we need to better understand the development of the disease. Presently, we do not know what triggers the abnormal immune activity in JRA/JIA that can lead to serious damage to joints, eyes, and other vital organs, and there are no markers in the blood or genes of children with arthritis that can help us to follow disease activity or to predict JIA outcome. Recent discovery of an antibody to the DEK protein in some children with JIA and related diseases holds great promise for improving our knowledge of how these conditions begin and how they might be treated more effectively. We recently identified DEK protein and antibodies in synovial fluids from patients. We also found that DEK protein is secreted by activated human macrophages by a process that is capable of eliciting antibodies against the DEK protein. The secretion of DEK is stimulated by lnterieukin-8, a protein that helps to recruit immune cells to an area of inflammation. In addition, dexamethasone and cyclosporin, two powerful anti-inflammatory medications used to treat autoimmune diseases, can block DEK secretion. We have also seen that the DEK protein itself can attract immune cells to an area of inflammation and, in this way may, increase the severity of the immune reaction. Now we suggest to further investigating in details the way DEK attracts immune cells by identifying the potential binding receptor/s for DEK. To identify the binding receptor/s to DEK we will perform in vitro migration assays using specific receptors inhibitors, immunoprecipitation and co-localization assays. To investigate DEK contribution to the development of the disease will use several known animal models for arthritis assess the effect of DEK protein and antibodies on the development of the disease. These insights are very important to our ability to develop a new strategy to the diagnosis/treatment of JIA, and to improve the present and future health of children with arthritis and related diseases.

描述（由申请人提供）：少年类风湿（或特发性）关节炎（JRA/JIA）是儿童残疾的最常见原因。即使是最温和的疾病形式，也具有关节变形和功能丧失的重大风险，预防了终生不适和残疾。该疾病在16岁以下的每200名中都会影响1个孩子。在童年时期控制该疾病对于防止JRA/JIA儿童的畸形和后来的残疾很重要。但是，目前的治疗范式强制使用侵略性，抗炎性药物具有潜在的有害副作用，这使得我们必须制定措施，以检测即时的疾病耀斑，并开发出更好的药物来治疗，副作用较少。为了实现这些目标，我们需要更好地了解疾病的发展。目前，我们不知道是什么触发了JRA/JIA中的异常免疫活性，这会导致关节，眼睛和其他重要器官的严重损害，并且关节炎儿童的血液或基因中没有标记，可以帮助我们遵循疾病活动或预测JIA的结果。最近在一些JIA和相关疾病的儿童中发现了DEK蛋白的抗体具有巨大的希望，可以提高我们对这些疾病的开始以及如何更有效治疗的知识。我们最近发现了来自患者的滑液中的DEK蛋白和抗体。我们还发现，DEK蛋白通过能够引起针对DEK蛋白的抗体的过程被激活的人类巨噬细胞分泌。 DEK的分泌是由Lnterieukin-8刺激的，该蛋白有助于将免疫细胞募集到炎症区域。此外，地塞米松和环孢菌素是两种用于治疗自身免疫性疾病的强大抗炎药，可以阻止DEK分泌。我们还看到，DEK蛋白本身可以吸引免疫细胞到炎症区域，并且这样可能会增加免疫反应的严重程度。现在，我们建议通过鉴定DEK的潜在结合受体来进一步研究DEK吸引免疫细胞的方式。为了鉴定与DEK的结合受体，我们将使用特定受体抑制剂，免疫沉淀和共定位测定法进行体外迁移测定。为了调查DEK对疾病发展的贡献，将使用几种已知的动物模型来评估DEK蛋白和抗体对疾病发展的影响。这些见解对于我们制定新策略来诊断/治疗JIA以及改善关节炎和相关疾病儿童的当前和未来健康非常重要。