Metabolomic Markers of Disease Activity and Therapeutic Response in Autoimmune Arthritis

自身免疫性关节炎疾病活动性和治疗反应的代谢组学标志物

• 批准号: 10115132
• 负责人: Ryan Sol Funk
• 金额: $ 22.53万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115132
• 关键词: Address; Age; Arthritis; Autoimmunity; Biochemical; Biochemical Markers; Biochemical Pathway; Biological Assay; Biological Markers; Blood specimen; Chronic; Chronic Childhood Arthritis; Clinical; Data; Development; Diagnostic; Disease; Disease Marker; Early treatment; Future; Goals; In Vitro; Individual; Institutes; Kansas; Laboratories; Metabolic; Metabolic Pathway; Methotrexate; Microfluidics; Mission; Modification; Morbidity - disease rate; Multi-site clinical study; Outcome; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Pharmacometabolomics; Pharmacotherapy; Population; Preparation; Process; Research; Research Proposals; Rheumatoid Arthritis; Safety; Sampling; Techniques; Testing; Tissues; Translational Research; Validation; assay development; autoimmune arthritis; base; clinical biomarkers; design; disability; disorder control; drug efficacy; effective therapy; improved; joint inflammation; metabolome; metabolomics; molecular marker; mouse model; multiplex assay; precision drugs; precision medicine; prevent; programs; response; skills; tool; treatment response

Autoimmune arthritis, in the form of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), is the most common rheumatic condition worldwide, and manifests as chronic joint inflammation that results in significant morbidity and disability. Methotrexate (MTX) continues to be the most widely used disease-modifying drug in the treatment of autoimmune arthritis, but is characterized by a slow onset of action along with an unpredictable response profile resulting in inadequate efficacy in approximately 1 out of every 3 patients treated. As a result, the treatment of RA and JIA frequently requires individual tailoring of drug therapy and is characterized by a 'trial-and-error' approach to therapy. Recognizing that early control of disease activity is a positive predictor of long-term outcomes, there remains a critical need to identify biomarkers to guide clinicians in the early selection and optimization of drug therapy in these patients. The goal of this project is to apply a translational metabolomics approach to identify molecular biomarkers of disease activity and MTX response in autoimmune arthritis. We hypothesize that both RA and JIA result in metabolic dysregulation with corresponding changes in metabolomic profiles that are associated with response to MTX, which therefore represent molecular markers that can be utilized to guide therapy in these patients. To test this hypothesis, we will utilize patient samples in combination with advanced techniques in metabolomics and biomarker assay development to address the following aims: 1) identify circulating metabolomic markers of disease in autoimmune arthritis, 2) identify circulating metabolomic markers of MTX response in autoimmune arthritis, and 3) develop a chip-based assay for the quantitation of molecular markers of MTX response in autoimmune arthritis. The candidate is a clinical pharmacologist with a proven commitment to the conduct of translational science to drive the mission of precision medicine in the treatment of autoimmune arthritis. The skills in metabolomics and bioanalytical assay development acquired through this proposal will facilitate the candidate's long-term goal to improve the safety and efficacy of drug therapies in the treatment of autoimmune arthritis through the establishment of a research program investigating the application of pharmaco-metabolomics as a strategy to personalize drug therapy in the treatment of RA and JIA.

以类风湿性关节炎（RA）和幼年特发性关节炎（JIA）的形式的自身免疫性关节炎是全世界最常见的风湿性病症，并且表现为导致显著发病率和残疾的慢性关节炎症。甲氨蝶呤（MTX）仍然是治疗自身免疫性关节炎中最广泛使用的疾病改善药物，但其特征在于起效缓慢，沿着不可预测的反应特征，导致每3名接受治疗的患者中约有1名疗效不足。因此，RA和JIA的治疗经常需要个体化的药物治疗，其特征在于“试错”治疗方法。认识到疾病活动的早期控制是长期结果的积极预测因素，仍然迫切需要确定生物标志物，以指导临床医生在这些患者中早期选择和优化药物治疗。本项目的目标是应用翻译代谢组学方法来鉴定自身免疫性关节炎中疾病活动和MTX反应的分子生物标志物。我们假设RA和JIA均导致代谢失调，代谢组学特征发生相应变化，与MTX反应相关，因此代表了可用于指导这些患者治疗的分子标志物。为了验证这一假设，我们将利用患者样本，结合代谢组学和生物标志物检测开发中的先进技术，以实现以下目标：1）鉴定自身免疫性关节炎中疾病的循环代谢组学标志物，2）鉴定自身免疫性关节炎中MTX应答的循环代谢组学标志物，和3）开发用于定量自身免疫性关节炎中MTX应答的分子标志物的基于芯片的测定。 候选人是临床药理学家，致力于转化科学的开展，以推动精准医学在治疗自身免疫性关节炎方面的使命。通过该提案获得的代谢组学和生物分析检测开发技能将促进候选人的长期目标，即通过建立一个研究项目，调查药物代谢组学的应用，以提高药物治疗在治疗自身免疫性关节炎中的安全性和有效性。