AIM-for-RA

RA 的 AIM

基本信息

批准号：
10595666
负责人：
Jennifer Howitt Anolik
金额：
$ 160万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
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/10595666
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 Classification Clinical Clinical Research Clinical Trials Complement Data Diagnosis Disease Disease Outcome Disease remission Disease-Modifying Second-Line Drugs Dissection Dissociation 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 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 Process 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 Tissue Sample Tissues Treatment Failure Treatment outcome United States National Institutes of Health Variant adverse outcome biobank 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 patient retention 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

项目摘要

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，其特点是炎症和关节损伤，通常会导致早期和晚期严重的残疾和疼痛该领域未满足需求的关键领域包括：1）高度异质和不可预测的病程，2) 持久缓解的罕见性，3) 目前可用的治疗方法失败实现低疾病活动度和/或限制许多患者进行性关节损伤，以及 4) 缺乏我们建议需要强有力的生物标志物来制定适当的治疗策略。滑膜组织中的细胞和分子变异是这种异质性的基础，并且理解以此为基础将改善对病程的预测，并为及时治疗提供依据。通过选择具有更高 RA 持续控制率的精准治疗策略。持续协作的全球团队科学，AIM-for-RA 团队已经开发出最新状态解构 RA 滑膜活检组织的最先进方案——一项深刻的创新对参与 RA 发病机制的细胞和途径的先进知识，确定了新的治疗方法然而，目前尚不清楚滑膜中的分子相互作用如何与定义的进化相关临床结果，从临床前危险期到关节炎发作，然后到滑膜炎因此，AIM-for-RA 疾病团队 (DT) 旨在将疾病相关的滑膜细胞联系起来。环境暴露、疾病结果和治疗的途径和动态串扰反应，从而重建疾病发病机制轨迹。使用协调方案对 9 个地点的 50 名 RA 患者进行基于滑膜活检的截面研究集成技术，Aim 1 将提供高质量的多模式临床表型和组织学数据以及滑膜组织和其他生物样本，以评估滑膜细胞和分子如何对这些个体进行纵向随访和重复活检。甲氨蝶呤单药治疗后，目标 2 将解决滑膜特征和多模式是否数据预测一线甲氨蝶呤对早期未接受治疗的患者的反应或失败最后，在目标 3 中，对于甲氨蝶呤反应不足的患者，我们将解决是否存在这种情况。不同的滑膜细胞或分子特征直接预测对生物疗法的积极反应针对这些特征，该计划的成果将具有快速转化的潜力。总体而言，协作，改善所有 RA 疾病阶段的治疗结果。全球 AIM-for-RA 团队对 RA 疾病发病机制进行了开创性观察非常适合解决关键问题并满足该领域未满足的主要需求。