Type I interferon Impacts Treatment Response in Rheumatoid Arthritis

类风湿关节炎(RA)是一种常见的多系统炎症状态。延误有效的治疗结果 增加发病率和死亡率，并造成沉重的经济负担。目前的治疗策略是经验性的 因为我们没有标记物表明哪种疗法对个人最好。肿瘤坏死因子抑制物 (TNFi)是RA最常见的初始生物治疗方法。回答各不相同，约有30% 无反应，另有30%只有部分反应。我们已经在测试和验证队列中表明 治疗前循环中的I型干扰素(T1干扰素)预测对TNFi无应答。治疗前干扰素-β对干扰素-α活性的影响 Ratio&gt；1.3强烈预测对TNFi无应答(在验证队列中，特异度=77%)。没有病人 比率&gt；1.3达到缓解或疾病活动度低。我们使用单细胞分析来研究血液单核细胞 干扰素-β/α活性比值高与低的类风湿关节炎患者(Mo)基因表达的差异 在两组之间，支持对关键效应细胞群体的下游影响。出席或缺席 JAK1的表达与干扰素-β/α比值呈正相关。类风湿关节炎时，血钼侵入滑膜，局部刺激 推动炎性巨噬细胞(Mφ)群体的扩张。目前尚不清楚循环中的干扰素比率 反映了滑膜中T1干扰素的水平和途径的激活，这将在目标1中进行检测。 血和滑膜信号在钼对炎症的渗出和分化中的相对作用 Mo/MφS不为人知。这一点将在目标2中使用一种新的可灌流的芯片上器官系统进行探索。 假设：RA TNFi无应答者血液和滑膜干扰素-β/α比率增加，导致改变 JAK1和干扰素刺激的基因表达，增加钼的侵染和分化为炎性 MφS。我将从两个具体目标来探索这一首要假设：(1)检测T1干扰素途径的差异 EULAR反应良好或无反应的类风湿关节炎患者滑膜的激活和组织病理学 TNFi。(2)检测干扰素-α和干扰素-β对RA-Mo、Mo来源的M-φ和成纤维细胞样滑膜细胞的影响。 我将获得有偏见和无偏见的分析、数据体系结构/人工智能以及使用 生物工程微生理系统询问人类类风湿关节炎生物学，我需要它成功发射 并确立自己作为独立研究员的地位，推动RA精准医学的发展。结果将提供 为未来的方向提供了肥沃的土壤。精选的课程工作将补充我的研究，增强我的技能。 介绍、出版和提交助学金将提高我的能力。我的目标是用细胞生物学、免疫学、 和当代方法，以了解类风湿患者之间的差异，并允许预测和 一种针对个人疾病和个人免疫学量身定做的治疗方法。纽约大学投入了大量的资金 促进基础、临床和转化性研究的资源和基础设施。高口径的密度 科学家和大学环境是ESI向独立过渡的理想环境。来自K08的支持至关重要 在我努力扩展我的研究技能和增强我的独立职业生涯中。

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.