Mechanisms of Insulin Resistance in Rheumatoid Arthritis

描述（由申请人提供）：类风湿关节炎（RA）患者患心血管（CV）疾病和胰岛素抵抗（一种代谢性CV危险因素）的风险增加。在没有类风湿关节炎的个体中，习惯性体育活动可改善胰岛素作用和心血管发病率。对于类风湿性关节炎患者，运动是否能带来类似的健康益处还没有研究。该建议概述了一个职业培训和研究计划，将为制定特定的干预措施提供基础，使体育活动可用于调节RA的代谢性CV风险。职业发展计划的重点是建立一个转化研究项目，应用最先进的技术在人群中进行机械研究。该计划的目标如下：1)发展与代谢相关的训练和技能；2)执行并熟练掌握骨骼肌活检技术；3)发展运动生理学和体育活动干预方面的专业知识；4)培养临床试验设计和实施的技能，并接受负责任的研究行为培训；5)培养先进的统计分析技能；6)提高论文准备和论文撰写的技能。我们假设ra相关的炎症和不活动介导骨骼肌萎缩和腹部肥胖增加，进而导致线粒体功能障碍和最终的胰岛素抵抗。这些假设将通过以下具体目的进行检验：1)确定与性别、年龄和bmi匹配的对照组相比，RA患者是否改变了身体成分并增加了脂肪分解；2)确定RA是否与参与肌肉萎缩的信号通路的激活升高和肌纤维成分的同步变化有关；3)确定RA患者肌内脂质失衡和/或线粒体功能障碍是否导致胰岛素信号受损；4)确定RA患者是否有胰岛素抵抗，相对于性别、年龄和bmi匹配的对照组，并评估RA患者胰岛素敏感性的预测因素，包括身体成分、脂肪分解和与肌肉萎缩和胰岛素脱敏相关的信号通路的激活。因此，这项工作将探索适用于类风湿性关节炎非药物治疗方法的创新假设，并实施一项全面的研究计划，旨在加深我们对人类疾病机制的理解。

DESCRIPTION (provided by applicant): Persons with rheumatoid arthritis (RA) are at increased risk of cardiovascular (CV) disease and insulin resistance, a metabolic CV risk factor. In individuals without RA, habitual physical activity improves insulin action and CV morbidity. The potential for exercise to confer similar health benefits in RA patients has not been explored. This proposal outlines a career training and research plan that will provide the basis for developing specific interventions whereby physical activity can be used to modulate metabolic CV risk in RA. The career development plan focuses on building a translational research program that applies state-of-the-art technology to perform mechanistic studies in human populations. The objectives of this plan are as follows: 1) To develop training and skills relevant to metabolism; 2) To perform and gain proficiency in skeletal muscle biopsy techniques; 3) To develop expertise in exercise physiology and physical activity interventions; 4) To develop skills in clinical trial design and implementation and obtain training in the responsible conduct of research; 5) To develop advanced skills in statistical analysis; and 6) To advance skills in manuscript preparation and grant writing. We hypothesize that RA-associated inflammation and inactivity mediate skeletal muscle atrophy and increased abdominal obesity, which in turn lead to mitochondrial dysfunction and eventual insulin resistance. These hypotheses will be tested via the following specific aims: 1) To determine whether persons with RA have altered body composition and increased lipolysis compared with sex-, age- and BMI-matched controls; 2) To determine whether RA associates with heightened activation of signaling pathways involved in muscle wasting and coincident changes in muscle fiber composition; 3) To determine whether intramuscular lipid imbalance and/or mitochondrial dysfunction in persons with RA contributes to impaired insulin signaling; and, 4) To determine whether persons with RA are insulin resistant, relative to sex-, age- and BMI-matched controls, and to evaluate predictors of insulin sensitivity in RA patients, including body composition, lipolysis, and activation of signaling pathways implicated in muscle wasting and insulin desensitization. Thus, this work will explore innovative hypotheses applicable to a non-pharmacologic treatment approach to RA, and implement a comprehensive research program that seeks to deepen our understanding of the mechanisms of human disease.