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.!

该计划项目的主要重点是免疫介导的炎症在发展中的作用 慢性关节炎以及如何调节这种炎症。尽管有很多链接的证据 免疫力和慢性炎性关节炎，特别是类风湿关节炎，缺乏有关如何的数据 启动免疫反应，哪些因素决定了它将如何发展，为什么它变为慢性以及如何 可以在没有长期免疫抑制的情况下解决慢性炎症。这个项目将使用 炎症性关节炎小鼠模型以解决这些问题。它提出了一个雄心勃勃的 但是高度专注的方法结合了三个相互关联的项目，这些项目由核心支持。没有动物模型 完美模仿人类类风湿关节炎；但是，它们可以复制疾病的重要方面 包括对于关节炎症和破坏很重要的途径。动物模型已经 在提供用于调节疾病的治疗方法的体内平台方面无价。经过 分析独特的模型，该项目将提供更集成的方法来阐明 关节炎的发病机理并克服任何单一模型的局限性。特别是该程序将 解决如何调节先天免疫反应。先天免疫反应是人体第一个的一部分 防御细菌和其他入侵者的防御线。人们认为关节炎可能是由 易感个体暴露于通常遇到的细菌成分。最近已经 发现蛋白激酶D1（PKD1）是该反应中关键信号通路中的关键中介。 该中介作用是通过将其他分子穿过细胞表面上的脂质筏。如果PKD1的相互作用 使用这些分子可以中断，可以预防关节炎。实现这一目标的新方法 提出了使用诱饵肽的中断。一旦炎症和关节炎发展，它们就是 通过持续的自身免疫反应永久存在。已经确定了几种可能是 负责此过程，但是很难建立特定反应的相对重要性。 确定特定反应的贡献的一种方法是特定的下调。使用人源化 类风湿关节炎易感基因的转基因的小鼠，该程序提出了创新的 自身免疫反应的特定下调方法。免疫反应基因与自身抗原耦合 肽将用于生成调节性T细胞。免疫反应的一般调节剂是维生素D。 长期以来，众所周知，维生素会调节钙稳态，但最近的发现表明 对于先天和特定自身免疫性，也可能具有重要的免疫调节性能。中的一个 提出的项目将与其他项目合作确定维生素D模拟的能力 维生素D具有调节自发性和诱导关节炎的高钙质特性。全部 该计划中的项目将使用专门提供统一高质量标准化的核心 分析每个项目。这将使项目之间的数据比较并实现大量 通过集中常用方法来节省。此外，核心将发展独立的科学 通过开发一种新方法来评估关节炎的存在和严重程度 用作治疗化合物的靶向输送系统的潜力。扩大研究基础 VAMC，每个组件项目都与外部专家启动了合作，该专家将提供 对提出的实验的补充见解。这些协作努力将有助于产生 智力兴奋和融洽的气氛。