Type I interferon Impacts Treatment Response in Rheumatoid Arthritis

I 型干扰素影响类风湿关节炎的治疗反应

• 批准号: 10525621
• 负责人: Theresa Wampler Muskardin
• 金额: $ 19.76万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525621
• 关键词: Affect; Architecture; Artificial Intelligence; Basic Science; Biological; Biological Assay; Biological Response Modifier Therapy; Biology; Biomedical Engineering; Biopsy; Biopsy Specimen; Blood; Blood Vessels; CSF1R gene; Caliber; Cells; Cellular biology; Clinical Research; Coculture Techniques; Complement; Cues; Data; Disease; Disease remission; Dissection; Economic Burden; Effector Cell; Environment; Fibroblasts; Flow Cytometry; Future; Gene Expression; Gene Expression Profiling; Genes; Grant; Histology; Histopathology; Human; Immunologics; Immunology; In Vitro; Individual; Inflammatory; Infrastructure; Institutes; Interferon Type I; Interferon-alpha; Interferon-beta; Interferons; Invaded; JAK1 gene; Lasers; Mass Spectrum Analysis; Measures; Mediator of activation protein; Modeling; Molecular; Morbidity - disease rate; Osteoclasts; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Population; Production; Proteins; Proteomics; Publishing; Research; Research Personnel; Resources; Rheumatoid Arthritis; Sampling; Scientist; Serum; Signal Transduction; Specificity; Stimulus; Stromal Cells; Synovial Cell; Synovial Membrane; System; TNF gene; Testing; Time; Tissues; Translational Research; Tumor-infiltrating immune cells; Validation; Work; career; cell type; clinically significant; cohort; cytokine; density; digital; effective therapy; experimental study; ineffective therapies; inhibitor; inhibitor therapy; loss of function; macrophage; microphysiology system; monocyte; mortality; novel; organ on a chip; partial response; patient subsets; peripheral blood; personalized approach; precision medicine; prevent; prognostication; response; single cell analysis; skills; treatment response; treatment strategy; tumor necrosis factor-alpha inhibitor

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.

类风湿性关节炎（RA）是一种常见的多系统炎症。延误有效的治疗结果