Type I interferon Impacts Treatment Response in Rheumatoid Arthritis

类风湿性关节炎（RA）是一种常见的多系统炎症性疾病。延迟有效治疗结果 发病率和死亡率增加，经济负担沉重。目前的治疗策略是经验性的 因为我们没有标记物来表明哪种疗法对个体最好。肿瘤坏死因子抑制剂 （TNFi）是RA最常见的初始生物治疗。答案是可变的，大约30% 没有反应，另外30%只有部分反应。我们已经在测试和验证队列中表明， 治疗前循环I型IFN（T1 IFN）预测对TNF 1无应答。处理前IFN-β对IFN-α的活性 比率>1.3强烈预测对TNFi无应答（在验证组中特异性=77%）。无患者 比率>1.3的患者获得缓解或疾病活动度低。我们用单细胞分析法研究血液单核细胞 (Mo)高与低IFN-β/α活性比RA患者的基因表达，发现主要差异 支持对关键效应细胞群体的下游效应。存在或不存在 JAK 1的表达与IFN-β与α的比例密切相关。在RA中，血钼侵入滑膜，局部刺激 驱动炎性巨噬细胞（Mφ）群体的扩张。目前尚不清楚是否循环IFN比率 反映了滑膜中的T1 IFN水平和途径激活，这将在目标1中进行检查。的 血液与滑膜信号在Mo渗出和分化为炎性细胞中的相对作用 Mo/Mφs未知。这将在Aim 2中使用新型灌注器官芯片系统进行探索。 假设：RA TNFi无应答者的血液和滑膜IFN-β/α比率增加，导致RA TNFi无应答者的免疫功能改变。 JAK 1和IFN-刺激基因的表达，增加的渗出和Mo向炎性细胞的分化 Mφs。我将在2个具体目标中探讨这一总体假设：（1）检测T1 IFN途径的差异 对EULAR反应良好或无反应的RA患者的滑膜中的活化和组织病理学进行了研究。 TNFi。(2)确定IFN-α和IFN-β对RA Mo、Mo衍生的Mφ和成纤维细胞样滑膜细胞的影响。 我将获得新的技能偏见和公正的分析，数据架构/人工智能，并在使用一个 生物工程微生理系统，以询问人类RA生物学，我需要成功启动 并使自己成为一名独立的研究人员，推动RA的精准医疗。结果将提供 为未来发展提供肥沃的土壤。选择课程将补充我的研究和巩固我的技能。 演讲，出版和提交赠款将提高我的能力。我打算用细胞生物学，免疫学， 和当代的方法来了解RA患者之间的差异，并允许解释和 针对个人疾病和个人免疫学的治疗方法。纽约大学投入巨资， 促进基础、临床和转化研究的资源和基础设施。高口径的密度 科学家和学院环境是理想的ESI过渡到独立。来自K 08的支持至关重要 在我努力扩展我的研究技能和授权我的独立职业生涯。

Rheumatoid arthritis (RA) is a common multisystem inflammatory condition. Delay in effective treatment results in increased morbidity and mortality, and a heavy economic burden. Current treatment strategies are empiric because we have no markers to suggest which therapy is best for an individual. Tumor necrosis factor inhibitors (TNFi) are the most common initial biologic treatment in RA. Responses are variable, with approximately 30% not responding and another 30% having only partial response. We have shown in test and validation cohorts that pre-treatment circulating type I IFN (T1IFN) predicts non-response to TNFi. Pre-treatment IFN-β to IFN-α activity ratio >1.3 was strongly predictive of non-response to TNFi (specificity=77% in the validation cohort). No patient with a ratio >1.3 achieved remission or low disease activity. We used single cell analysis to study blood monocyte (Mo) gene expression in RA patients with high vs. low IFN-β-to-α activity ratio and found major differences between the groups, supporting downstream effects upon a critical effector cell population. Presence or absence of JAK1 expression strongly aligned with IFN-β-to-α ratio. In RA, blood Mo invade synovium, and local stimuli drive expansion of inflammatory macrophage (Mφ) populations. It is not known whether the circulating IFN ratio in RA reflects T1IFN levels and pathway activation in the synovium, and this will be examined in Aim 1. The relative contributions of blood vs. synovial signals in the diapedesis and differentiation of Mo to inflammatory Mo/Mφs is not known. This will be explored in Aim 2 using a novel perfusable organ-on-a-chip system. HYPOTHESIS: RA TNFi non-responders have increased blood and synovial IFN-β/α ratio that results in altered expression of JAK1 and IFN-stimulated genes, increased diapedesis and differentiation of Mo into inflammatory Mφs. I will explore this overarching hypothesis in 2 Specific Aims: (1) Detect differences in T1IFN, pathway activation, and histopathology in synovium of RA patients who have a EULAR good response or no response to TNFi. (2) Determine the impact of IFN-α and IFN-β on RA Mo, Mo-derived Mφ, and fibroblast-like synoviocytes. I will gain new skills biased and unbiased analyses, data architecture/artificial intelligence, and in use of a bioengineered microphysiological system to interrogate human RA biology, which I need to successfully launch and establish myself as an independent investigator advancing precision medicine in RA. Results will provide fertile ground for future directions. Select coursework will complement my research and fortify my skills. Presenting, publishing, and submitting grants will sharpen my abilities. I aim to use cell biology, immunology, and contemporary approaches to understand differences among RA patients and allow for prognostication and a treatment approach tailored to an individual’s disease and personal immunology. NYU is heavily invested with the resources and infrastructure to promote basic, clinical and translational research. The density of high caliber scientists and collegial environment is ideal for an ESI transitioning to independence. Support from a K08 is vital in my efforts to expand my research skills and empower my independent career.