Skeletal muscle biology in rheumatoid arthritis

类风湿性关节炎的骨骼肌生物学

• 批准号: 8220488
• 负责人: Leslie J Crofford
• 金额: $ 40.42万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-17 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8220488
• 关键词: Activities of Daily Living; Address; Adverse effects; Affect; Animal Experiments; Animals; Antimetabolites; Antioxidants; Area; Arthralgia; Biochemical; Biological; Biology; Blood Circulation; Calcium; Chronic; Clinical; Collagen Arthritis; Data; Depressed mood; Disease; Endocrine; Event; Experimental Arthritis; Experimental Models; Exposure to; Folic Acid Antagonists; Functional disorder; Future; Goals; Homeostasis; Human; Hygiene; Individual; Inflammatory; Injury; Interleukins; Intervention; Joints; Limb structure; Link; Mediator of activation protein; Modeling; Mus; Muscle; Muscle Fibers; Muscle Mitochondria; Muscle Weakness; Muscle function; Muscular Atrophy; Neurons; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Oxidants; Oxidation-Reduction; Oxidative Stress; Patients; Peroxonitrite; Pharmacologic Substance; Pharmacotherapy; Population; Process; Production; Proteins; Quality of life; Reactive Oxygen Species; Research; Rheumatoid Arthritis; Ryanodine; Skeletal Muscle; Source; Sterile coverings; Stimulus; Sulfhydryl Compounds; Symptoms; Testing; Therapeutic; Tissues; Tumor Necrosis Factor-alpha; Walking; arthritis therapy; clinical care; clinically relevant; cytokine; design; drug development; falls; joint stiffness; mouse model; research study; response; standard of care

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is the most common chronic inflammatory disease, affecting up to 1% of the population. Beyond joint pain and stiffness, muscle weakness is among the most prevalent symptoms of RA patients. Weakness affects most major muscle groups and limits basic activities such as walking, sitting and rising from chairs, opening containers, dressing oneself, and personal hygiene. Weakness also contributes to postural instability in RA, predisposing individuals to fall-related injuries, and dramatically lessens the overall quality of life. There is no drug therapy for RA-related weakness, no clinical standard of care to address this debilitating problem. The goal of this project is to define processes that cause weakness in RA and identify biological targets for future drug development. Weakness far exceeds muscle atrophy in RA patients. Therefore, the focus of our project is loss of contractile function as reflected by specific force, i.e, force per cross-sectional area. Our experimental model proposes that RA increases muscle exposure to proinflammatory cytokines that stimulate production of nitric oxide (NO) derivatives and reactive oxygen species (ROS) by muscle fibers. The resulting oxidative stress depresses specific force and causes weakness. Interventions that disrupt this chain of events are expected to preserve specific force, opposing RA-related weakness. We will test this model by using muscles from RA patients and a well-established mouse model of RA (collagen-induced arthritis, CIA) to address four specific aims: Specific Aim 1. To identify cytokines essential for RA-induced weakness. Specific Aim 2. To define changes in skeletal muscle oxidant production caused by RA. Specific Aim 3. To define cellular mechanisms of contractile dysfunction in RA. Specific Aim 4.To test therapeutic approaches for preserving muscle function in RA. PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis (RA) is the most common chronic inflammatory disease. Muscle weakness is among the most prevalent symptoms, limiting basic activities of daily living, predisposing individuals to fall-related injuries, and lessening the quality of life. The goal of this project is to define the processes that cause weakness in RA and identify biological targets for future drug development.

描述（由申请人提供）：类风湿性关节炎 (RA) 是最常见的慢性炎症性疾病，影响高达 1% 的人口。除了关节疼痛和僵硬之外，肌肉无力是 RA 患者最常见的症状之一。无力会影响大多数主要肌肉群，并限制基本活动，例如行走、坐下、从椅子上站起来、打开容器、穿衣和个人卫生。虚弱还会导致 RA 中的姿势不稳定，使个人容易遭受跌倒相关的伤害，并显着降低整体生活质量。目前尚无治疗 RA 相关虚弱的药物疗法，也没有临床护理标准来解决这一令人衰弱的问题。该项目的目标是定义导致 RA 弱点的过程，并确定未来药物开发的生物靶点。 RA 患者的虚弱程度远远超过肌肉萎缩。因此，我们项目的重点是收缩功能的丧失，如比力（即单位横截面积的力）所反映的那样。我们的实验模型提出，RA 增加肌肉对促炎细胞因子的暴露，刺激肌肉纤维产生一氧化氮 (NO) 衍生物和活性氧 (ROS)。由此产生的氧化应激会抑制特定的力量并导致虚弱。扰乱这一系列事件的干预措施预计将保留特定的力量，对抗与 RA 相关的弱点。我们将使用 RA 患者的肌肉和成熟的 RA（胶原诱导性关节炎，CIA）小鼠模型来测试该模型，以实现四个具体目标： 具体目标 1. 识别 RA 引起的无力所必需的细胞因子。具体目标 2. 确定 RA 引起的骨骼肌氧化剂产生的变化。具体目标 3. 明确 RA 收缩功能障碍的细胞机制。具体目标 4. 测试保留 RA 肌肉功能的治疗方法。 公众健康相关性：类风湿性关节炎 (RA) 是最常见的慢性炎症性疾病。肌肉无力是最常见的症状之一，它限制了日常生活的基本活动，使个人容易遭受跌倒相关的伤害，并降低生活质量。该项目的目标是确定导致 RA 弱点的过程，并确定未来药物开发的生物靶点。