Program Project for Mechanisms and Treatment of Arthritis

关节炎的机制和治疗计划项目

• 批准号: 8246345
• 负责人: DAVID D. BRAND
• 金额: --
• 依托单位: MEMPHIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8246345
• 关键词: Adaptor Signaling Protein; Address; Affect; Animal Model; Animals; Arthritis; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Bacteria; Biological; Biological Response Modifiers; Body part; Breeding; Calcium; Caring; Cartilage; Cell physiology; Cell surface; Chronic; Clinic; Collaborations; Collagen Arthritis; Complex; Coupled; Data; Development; Disease; Down-Regulation; Evaluation; Flow Cytometry; Gene Expression Profiling; Goals; Granulomatous; Haplotypes; Homeostasis; Human; IRAK1 gene; Image; Immune; Immune Response Genes; Immune response; Immune system; Immunity; Immunosuppression; Individual; Inflammation; Injection of therapeutic agent; Injury; Interleukin-1; Interruption; Knowledge; Lead; Link; Malignant Neoplasms; Mediating; Membrane Microdomains; Methods; Modeling; Monoclonal Antibodies; Mus; Musculoskeletal Diseases; NF-kappa B; Natural Immunity; Pathogenesis; Pathway interactions; Patients; Peptides; Population; Predisposition; Process; Property; Protein Kinase; Protein Kinase Interaction; Reaction; Receptor Signaling; Recruitment Activity; Regulation; Regulatory T-Lymphocyte; Relative (related person); Research; Research Personnel; Rheumatoid Arthritis; Role; Savings; Services; Severities; Signal Pathway; Signal Transduction; Site; Speed; Staging; Susceptibility Gene; System; Testing; Therapeutic; Toll-Like Receptor Pathway; Toll-like receptors; Transgenic Mice; Translations; Tropism; Veterans; Vitamin D; Vitamin D Analog; Vitamins; adaptive immunity; base; congenic; cost; human disease; in vivo; innovation; insight; instrumentation; interest; joint destruction; mouse model; novel; novel strategies; novel therapeutic intervention; novel therapeutics; operation; planetary Atmosphere; prevent; programs; research study; response; targeted delivery; transcription factor

The central focus of this Program Project is the role of immune mediated inflammation in the development of chronic arthritis and how that inflammation can be regulated. In spite of a preponderance of evidence linking immunity and chronic inflammatory arthritis, in particular rheumatoid arthritis, there is a lack of data on how that immune response is initiated, what factors determine how it will progress, why it becomes chronic, and how chronic inflammation can be resolved without long term immunosuppression. This project will use a combination of mouse models of inflammatory arthritis to address these questions. It proposes an ambitious but highly focused approach incorporating three interrelated projects supported by a core. No animal model perfectly mimics human rheumatoid arthritis; however, they can reproduce important aspects of disease including pathways that are important for joint inflammation and destruction. Animal models have been invaluable in providing an in vivo platform for testing of therapeutic approaches to regulate disease. By analyzing uniquely different models, this project will provide a more integrated approach to elucidation of the pathogenesis of arthritis and overcome the limitations of any single model. In particular the Program will address how innate immune reactions can be regulated. Innate immune reactions are part of the body's first line of defense in protection against bacteria and other invaders. It is thought that arthritis may be triggered by exposure of susceptible individuals to commonly encountered bacterial components. It has recently been discovered that protein kinase D1 (PKD1) is a key intermediary in a critical signaling pathway in that response. This intermediary acts by shuttling other molecules into lipid rafts on the cell surface. If the interaction of PKD1 with these molecules can be interrupted, arthritis may be prevented. A novel method for accomplishing this interruption using decoy peptides is proposed. Once inflammation and arthritis have developed, they are perpetuated by ongoing autoimmune reactions. Several autoantigens have been identified that may be responsible for this process but the relative importance of particular reactions has been difficult to establish. One way to ascertain the contribution of a particular reaction is by specific downregulation. Using humanized mice that are transgenic for rheumatoid arthritis susceptibility genes, this program proposes an innovative method of specific downregulation of autoimmune reactions. Immune response genes coupled to autoantigenic peptides will be used to generate regulatory T cells. A general regulator of immune reactions is Vitamin D. This vitamin has long been known to regulate calcium homeostasis but recent discoveries have suggested that it may also have important immune regulatory properties for both innate and specific autoimmunity. One of the projects proposed will determine, in collaboration with the other projects, the ability of a vitamin D analog that does not have the hypercalcemic property of vitamin D to regulate both spontaneous and induced arthritis. All of the projects in the Program will use a core dedicated to providing uniformly high quality standardized analyses to each project. This will enable comparison of data among the projects and realize substantial savings by centralizing commonly used methods. In addition the core will develop an independent scientific direction by developing a novel method for both evaluation of the presence and severity of arthritis with the potential for use as a targeted delivery system for therapeutic compounds. To expand the research base of the VAMC, each of the component projects has initiated collaboration with an external expert who will provide addition insights into the proposed experiments. These collaborative efforts will serve to generate an atmosphere of intellectual excitement and rapport.!

该计划项目的重点是免疫介导的炎症在疾病发展中的作用 慢性关节炎以及如何调节炎症。尽管有大量证据表明 免疫与慢性炎症性关节炎，特别是类风湿性关节炎之间的关系，目前缺乏关于如何影响免疫的数据。 免疫反应被启动，哪些因素决定了它如何发展，为什么它变成慢性，以及如何 慢性炎症无需长期免疫抑制即可得到解决。该项目将使用一个 结合炎症性关节炎小鼠模型来解决这些问题。它提出了一个雄心勃勃的 但高度集中的方法结合了由一个核心支持的三个相互关联的项目。无动物模型 完美模仿人类类风湿关节炎；然而，它们可以重现疾病的重要方面 包括对关节炎症和破坏很重要的途径。动物模型已 对于提供一个用于测试调节疾病的治疗方法的体内平台而言，这是非常宝贵的。经过 通过分析独特的不同模型，该项目将提供一种更加综合的方法来阐明 关节炎的发病机制并克服任何单一模型的局限性。特别是该计划将 解决如何调节先天免疫反应。先天免疫反应是身体第一反应的一部分 抵御细菌和其他入侵者的防线。据认为，关节炎可能是由 易感个体暴露于常见细菌成分。最近已经是 发现蛋白激酶 D1 (PKD1) 是该反应中关键信号通路的关键中介。 这种中介通过将其他分子穿梭到细胞表面的脂筏中来发挥作用。如果 PKD1 相互作用 通过这些分子可以被阻断，关节炎就可以得到预防。实现这一目标的新颖方法 建议使用诱饵肽进行中断。一旦出现炎症和关节炎， 由于持续的自身免疫反应而持续存在。已鉴定出多种自身抗原，可能是 负责这一过程，但特定反应的相对重要性一直难以确定。 确定特定反应的贡献的一种方法是通过特定的下调。使用人性化 类风湿性关节炎易感基因转基因小鼠，该项目提出了一种创新方法 特异性下调自身免疫反应的方法。与自身抗原偶联的免疫反应基因 肽将用于产生调节性T细胞。免疫反应的一般调节剂是维生素 D。 人们早就知道维生素可以调节钙稳态，但最近的发现表明它 还可能对先天性和特异性自身免疫具有重要的免疫调节特性。中的一个 拟议的项目将与其他项目合作，确定维生素 D 类似物的能力 不具有维生素 D 的高钙特性来调节自发性关节炎和诱发性关节炎。全部 该计划中的项目将使用致力于提供统一高质量标准化的核心 对每个项目进行分析。这将使项目之间的数据进行比较并实现实质性 通过集中常用方法来节省成本。此外，核心还将开发独立的科学 通过开发一种评估关节炎的存在和严重程度的新方法来指导方向 用作治疗化合物的靶向递送系统的潜力。扩大研究基地 VAMC，每个组成项目都已启动与外部专家的合作，该专家将提供 对所提出的实验的额外见解。这些合作努力将有助于产生 知识分子兴奋和融洽的气氛。！