AIM-for-RA

RA 的 AIM

• 批准号: 10451387
• 负责人: Jennifer Howitt Anolik
• 金额: $ 90万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-22 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10451387
• 关键词: 3-Dimensional; Address; Affect; Algorithms; Architecture; Area; Arthritis; Artificial Intelligence; Autoantibodies; Autoimmune; B-Lymphocytes; Binding; Biological; Biological Markers; Biological Response Modifier Therapy; Biopsy; Cell Communication; Cells; Characteristics; Clinical; Clinical Research; Clinical Trials; Complement; Data; Diagnosis; Disease; Disease Outcome; Disease remission; Disease-Modifying Second-Line Drugs; Dissection; Drug Targeting; Early treatment; Enrollment; Ensure; Environmental Exposure; Evolution; Failure; Fibroblasts; Flare; Funding; Generations; Goals; Heterogeneity; Histology; Image; Immune; Immune system; In Situ; Individual; Inflammation; Inflammatory; Knowledge; Longitudinal Studies; Measurement; Mediator of activation protein; Methotrexate; Molecular; Molecular Analysis; Onset of illness; Oranges; Outcome; Pain; Pathogenesis; Pathogenicity; Pathologic Processes; Pathway interactions; Patient Care; Patient Recruitments; Patients; Pattern; Phenotype; Population; Positioning Attribute; Precision therapeutics; Preparation; Prevention strategy; Protocols documentation; Psoriatic Arthritis; Research Personnel; Rheumatoid Arthritis; Risk; Role; Sampling; Science; Selection for Treatments; Seminal; Site; Specimen; Synovial Cell; Synovial Fluid; Synovial Membrane; Synovitis; Systemic Lupus Erythematosus; Technology; Time; Tissue Sample; Tissues; Treatment Failure; Treatment outcome; United States National Institutes of Health; Variant; adverse outcome; base; bone cell; clinical phenotype; cohort; design; disability; disorder prevention; effector T cell; epigenetic regulation; follow-up; high dimensionality; improved; individualized medicine; innovation; joint inflammation; joint injury; monocyte; multimodal data; multimodality; novel; personalized therapeutic; phenotypic data; pre-clinical; prevent; prognostic; programs; reconstruction; response; small molecule; standard of care; tissue reconstruction; transcriptomics; translational applications; treatment response; treatment strategy

Rheumatoid arthritis (RA) affects approximately 1% of the population and is characterized by inflammation and joint damage, often leading to considerable disability and pain in both early and established stages. Key areas of unmet need in the field include the: 1) highly heterogeneous and unpredictable disease course, 2) rarity of lasting remissions, 3) failure of currently available treatments to achieve low disease activity and/or limit progressive joint damage in many patients, and 4) lack of robust biomarkers necessary to personalize appropriate treatment strategies. We propose that cellular and molecular variation in synovial tissue underlies this heterogeneity and that understanding the basis for this will improve the prediction of disease course and provide a rationale for the timely selection of precision treatment strategies with higher rates of sustained RA control. Through sustained collaborative global team-science, the AIM-for-RA Team has already developed state-of- the-art protocols that deconstructed RA synovial biopsy tissues - an innovation that profoundly advanced knowledge in cells and pathways involved in RA pathogenesis, identified novel treatment targets, identified disease biomarkers, and opened new opportunities in disease prevention. However, it remains unclear how molecular interactions in the synovium relate to the evolution of defined clinical outcomes, from the at-risk preclinical period to arthritis onset, and then through to synovitis outcome. Therefore, AIM-for-RA Disease Team (DT) aims to relate disease-relevant synovial cellular pathways and dynamic crosstalk to environmental exposures, disease outcomes and treatment response, thereby reconstructing the disease pathogenesis trajectory. In a DMARD-naïve RA cross- sectional synovial biopsy-based study of 50 RA patients across 9 sites using harmonized protocols and integrated technologies, Aim 1 will deliver high-quality multimodal clinical phenotype and histology data, along with synovial tissue and other biosamples, to evaluate how synovial cellular and molecular pathways relate to disease onset. With longitudinal follow-up and repeat biopsy of these individuals after methotrexate monotherapy, Aim 2 will address whether synovial signatures and multi-modal data predict first-line methotrexate response, or failure in patients with early previously untreated disease. Finally, in Aim 3, in patients with methotrexate inadequate response we will address whether distinct synovial cellular or molecular features predict a positive response to biologic therapies directly targeting these features. The outcomes of this program will have potential for rapid translational application to improve treatment outcomes at all RA disease stages. Collectively, the collaborative, global AIM-for-RA Team that has made seminal observations regarding RA disease pathogenesis is ideally suited to inform the key questions and meet major unmet needs in the field.

类风湿性关节炎（RA）影响大约1%的人口，其特征是