Protein tyrosine phosphatases as rheostats of Jak-STAT cytokine signals and determinants of disease heterogeneity.

炎症是身体对感染或损伤的反应，有助于愈合过程。在免疫介导的疾病中，如类风湿性关节炎，对炎症的适当控制丧失，促进关节疾病。患有这些疾病的患者通常表现出基础病理学的差异，影响疾病发作的速率、严重程度和对治疗的反应。这里概述的研究将定义驱动疾病中这些差异的炎症机制。采用新开发的关节炎模型，这些模型显示出与类风湿性关节炎中三种形式的关节炎症相当的疾病特征，我们将确定负责引导病理过程的炎症级联反应中的决策过程。因此，该研究旨在产生与这种衰弱性疾病的诊断和治疗相关的新假设。问题的背景是什么？细胞因子是调节炎症的蛋白质，被认为是治疗类风湿性关节炎的主要药物靶点。这些抑制剂靶向驱动关节炎症和疾病进展的不良细胞因子活性。然而，并非所有患者都对这些药物有反应，这表明多种通常独立的机制导致关节疾病。我们认为，细胞因子引导类风湿患者中所见的炎性关节疾病的类型。增加对导致这种多样性的炎症过程的理解将改善患者的诊断和临床决策，从而为患者提供最佳治疗方案。我们以前确定了一种调节机制，改变了炎症关节内细胞对细胞因子信号的感知和解释方式。我们认为这种机制影响了关节疾病的模式和严重程度。因此，该项目旨在：1.慢性关节疾病的炎症机制是什么？2.特定细胞因子的活性如何影响观察到的关节炎症类型？3.如何控制细胞因子信号以确定疾病的进程和关节病理学？4.从小鼠疾病模型中获得的见解能否增加对人类不同形式关节炎症如何发生的理解？实验计划是什么？研究将确定细胞因子如何促进在患者中观察到的各种形式的关节炎症。在这里，炎症的差异是指患病组织内浸润免疫和结构细胞的组成和特定组织。检查这些细胞对细胞因子的反应，实验将使用基于细胞的系统和关节炎小鼠模型来识别基因表达的差异，影响这些基因变化的机制以及这些事件对关节炎症的影响。为了检验任何发现与人类疾病的相关性，我们将使用超声引导下的类风湿关节炎患者组织活检来产生影响类风湿关节炎临床治疗的新假设。阻断细胞因子的生物药物和小分子抑制剂已经彻底改变了免疫介导的疾病（如类风湿性关节炎）的治疗。然而，患者经常表现出对治疗的反应不足，并且经常对某些类别的治疗表现出不同的疗效。这种治疗反应的缺乏可能反映了影响关节炎患者的疾病亚型谱的临床特征。提高我们对关节炎病理学的理解，我们将确定类风湿性关节炎疾病异质性的细胞和分子过程。通过这项研究获得的新见解将产生关于关节炎发展的新假设，并为未来的临床研究开辟新的机会。

Inflammation is the body's response to infection or injury and contributes to the healing process. In immune-mediated diseases such as rheumatoid arthritis, appropriate control of inflammation is lost, promoting joint disease. Patients with these diseases often display differences in the underlining pathology, affecting the rate of disease onset, the severity, and response to therapy. Studies outlined here will define the inflammatory mechanisms driving these differences in disease. Adopting newly developed models of arthritis that display disease hallmarks comparable with three forms of joint inflammation in rheumatoid arthritis, we will identify the decision-making process within the inflammatory cascade responsible for steering the course of pathology. The study is therefore designed to generate new hypotheses relevant to the diagnosis and treatment of this debilitating condition. What is the background to the problem?Cytokines are proteins that regulate inflammation and are considered major drug targets for the treatment of rheumatoid arthritis. These inhibitors target adverse cytokine activities driving joint inflammation and disease progression. However, not all patients respond to these drugs, suggesting that multiple, often independent, mechanisms contribute to joint disease. We propose that cytokines steer the type of inflammatory joint disease seen in rheumatoid patients. Increased understanding of the inflammatory processes responsible for this level of diversity will improve patient diagnosis and clinical decisions on the best course of patient therapy.What are the research questions? We previously identified a regulatory mechanism that alters the way cytokine cues are sensed and interpreted by cells within the inflamed joint. We propose that this mechanism affects the pattern and severity of the joint disease. The project is, therefore, designed to:1. What are the inflammatory mechanisms that drive chronic joint disease?2. How do the activities of particular cytokines affect the type of joint inflammation observed?3. How are cytokine signals controlled to determine the course of the disease and joint pathology?4. Can insights from mouse models of disease increase understanding of how different forms of joint inflammation arise in humans?What is the experimental plan? Studies will establish how cytokines promote the various forms of joint inflammation observed in patients. Here, differences in inflammation refer to the composition and specific organization of infiltrating immune and structural cells within the diseased tissue. Examining the response of these cells to cytokines, experiments will use cell-based systems and mouse models of arthritis to identify differences in gene expression, the mechanisms that affect these gene changes and the impact of these events on joint inflammation. Testing the relevance of any discoveries to human disease, we will use ultrasound-guided tissue biopsies from rheumatoid arthritis patients to generate new hypotheses affecting the clinical management of rheumatoid arthritis.Why is this particular study important? Biological drugs and small molecule inhibitors that block cytokines have revolutionised the treatment of immune-mediated diseases such as rheumatoid arthritis. However, patients often show inadequate responses to treatment and frequently display varying efficacies to certain classes of therapy. This lack of therapeutic response may reflect the clinical characterisation of a spectrum of disease subtypes affecting arthritis patients. Enhancing our understanding of arthritis pathology, we will identify the cellular and molecular processes of disease heterogeneity in rheumatoid arthritis. New insights captured through this study will generate new hypotheses on the development of arthritis and open new opportunities for future clinical investigation.