Targeting Molecular Transducers of Exercise for Osteoarthritis Therapies

靶向运动分子传感器治疗骨关节炎

• 批准号: 10516067
• 负责人: TIMOTHY M GRIFFIN
• 金额: --
• 依托单位: OKLAHOMA CITY VA 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: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10516067
• 关键词: Acute; Address; Adipose tissue; Affect; Agonist; Analgesics; Animal Model; Animals; Anti-Inflammatory Agents; Arthralgia; Biological; Biological Response Modifier Therapy; Chronic; Consumption; Coupling; Cumulative Trauma Disorders; Data; Degenerative polyarthritis; Development; Disease; Drug Design; Drug Targeting; Environment; Exercise; Exercise Therapy; Fatty Acids; Fatty acid glycerol esters; Fibrosis; Flow Cytometry; General Population; Glucose; Glycolysis; Goals; Hand; Health; Histopathology; Image; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Injury; Intervention; Joints; Knee; Knee Osteoarthritis; Knee joint; Knowledge; Lipids; Lipolysis; Macrophage; Macrophage Activation; Measures; Medial meniscus structure; Mediating; Metabolic; Metabolism; Methods; Modeling; Molecular; Molecular Target; Mus; Nociception; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Opioid; Oral; Outcome; PPAR gamma; Pain; Pain management; Pharmaceutical Preparations; Pharmacological Treatment; Phenotype; Physical Exercise; Physical therapy; Pre-Clinical Model; Production; Regenerative Medicine; Research; Resolution; Risk; Running; Synovial Fluid; Synovial Membrane; Synovial joint; Testing; Therapeutic Effect; Therapeutic Uses; Time; Tissue Engineering; Tissues; Transducers; Trauma; Traumatic Arthropathy; Veterans; active duty; cytokine; disability; engineered stem cells; exercise intervention; fatty acid metabolism; fatty acid oxidation; functional improvement; functional outcomes; gait examination; genetic approach; improved; improved outcome; in vivo; innovation; instrument; joint inflammation; lipid biosynthesis; lipid metabolism; mechanical allodynia; meniscus injury; mouse genetics; mouse model; nanoparticle; novel strategies; novel therapeutic intervention; novel therapeutics; osteoarthritis pain; pharmacologic; physically handicapped; prevent; response; rosiglitazone; side effect; tissue-repair responses; treadmill; uptake

Osteoarthritis (OA) disproportionately affects veterans, resulting in more pain and functional limitations compared to the general population. No disease-modifying treatments exist for OA, and current pain medications (e.g., opioids and NSAIDs) have limited long-term efficacy and adverse side effects. Unresolved cellular and molecular joint inflammation is recognized as the central mechanism of OA progression. However, a barrier to progress in the field is identifying the causes of chronic OA inflammation and how to resolve them. The applicant's long-term goal for overcoming this barrier is to understand the molecular mechanisms of how exercise therapy reduces OA inflammation and pain so that synergistic drug targets can be identified and developed for therapeutic use. The premise of this application is that macrophages depend on lipid metabolism reprogramming to complete anti-inflammatory alternative activation. The objective here is to determine how intra-articular adipose tissue lipolysis modifies joint inflammation by regulating anti-inflammatory macrophage polarization. The central hypothesis is that the resolution of joint inflammation requires the temporal coupling of infra-patellar fat pad (IFP) lipolysis with macrophage lipid uptake and fatty acid metabolism to drive alternative activation. This hypothesis has been developed based on the applicant's exciting preliminary data showing that exercise triggers a transient induction of pro-inflammatory cytokines and macrophages in the knee synovium and IFP, which fully resolves by day 14 of running. Notably, the induction and resolution of inflammation occurs in parallel with a transient cycle of IFP lipolysis, fibrosis, and lipogenesis. The rationale for the proposed research is that an understanding of the causal relationship between joint tissue metabolites and cellular inflammatory mediators has the potential to generate new therapeutic opportunities by advancing fundamental knowledge about how joint inflammation is regulated. With strong preliminary data and expertise in small animal exercise, metabolism, and OA studies, the applicant will test the hypothesis by pursuing three specific aims: 1) Determine how intra-articular adipose tissue lipolysis mediates macrophage activation, joint inflammation, and post-traumatic OA; 2) Determine the effect of macrophage lipid uptake and fatty acid oxidation on joint inflammation and the development of post-traumatic OA; and 3) Develop a combined physical and biologic intervention strategy targeting lipid metabolism to reduce joint inflammation and pain in a pre-clinical model of chronic knee OA. Aims 1 and 2 will be tested in mouse models of resolving and non- resolving joint inflammation using wheel running and destabilization of the medial meniscus (DMM) models, respectively. The models, which have been established as feasible in the applicant's hands, will be used to test causal mechanisms that establish the pro- or anti-resolving effects of intra-articular lipids on joint inflammation. In aim 1, these include an inducible genetic approach to block lipolysis in the joint or a pharmacologic approach to enhance lipolysis. In the second aim, an inducible genetic approach will be used to inhibit peroxisome proliferator activated receptor-γ (PPARγ) in macrophages or stimulate PPARγ pharmacologically. The third aim combines physical and PPARγ pharmacologic treatments in the DMM model to test for synergistic interactions that improve pain and function more than exercise alone. By focusing on the cellular and molecular transducers of OA exercise therapy, the proposed research tests new, innovative paradigms for designing drugs to potentiate the therapeutic effects of OA exercise therapy. The proposed research is significant because it will initiate the systematic study of how synovial joint metabolism may be manipulated to promote the resolution of joint inflammation. This knowledge is also expected to be important for other OA therapies, such as optimizing the joint environment to support stem cell and tissue-engineering-based regenerative medicine strategies.

骨关节炎（OA）不成比例地影响退伍军人，导致更多的疼痛和功能局限性 与普通人群相比。没有针对OA的疾病改良治疗，目前的疼痛 药物（例如阿片类药物和NSAID）的长期有效性和不良副作用有限。未解决 细胞和分子关节注射被认为是OA进展的中心机制。然而， 该领域进步的障碍是确定注射慢性OA的原因以及如何解决它们。 申请人克服这一障碍的长期目标是了解分子机制 运动疗法可减少OA注射和疼痛，以便可以识别出协同的药物靶点 为治疗用途而开发。该应用的前提是巨噬细胞取决于脂质代谢 重编程以完成抗炎替代激活。这里的目的是确定如何 通过调节抗炎巨噬细胞调节关节内脂肪组织脂解的关节注射 极化。中心假设是联合注射的分辨率需要暂时耦合 巨噬细胞脂肪摄入和脂肪酸代谢的脂肪垫（IFP）脂解（IFP）脂解 激活。该假设是根据申请人令人兴奋的初步数据提出的。 运动触发膝关节促炎细胞因子和巨噬细胞的短暂诱导 和IFP，它可以在跑步的第14天完全解决。值得注意的是，炎症的诱导和分辨率发生 与IFP脂解，纤维化和脂肪形成的瞬时循环平行。提议的理由 研究是对关节组织代谢产物与细胞之间因果关系的理解 炎症介质有可能通过促进基本来创造新的治疗机会 有关如何调节关节感染的知识。具有强大的初步数据和小专业知识 动物运动，代谢和OA研究，申请人将通过追求三个特定的特定来检验该假设 目的：1）确定关节内脂肪组织脂解如何介导巨噬细胞激活，关节 炎症和创伤后的OA； 2）确定巨噬细胞脂质摄取和脂肪酸的影响 关节注射和创伤后OA的氧化； 3）共同开发 靶向脂质代谢的物理和生物学干预策略，以减轻关节感染和疼痛 慢性膝盖OA的临床前模型。目标1和2将在鼠标模型中测试和非 - 使用车轮跑步和中位弯面板（DMM）模型的稳定性解决关节炎症， 分别。这些模型已在申请人的手中确定为可行的模型，将用于测试 建立关节内脂质对关节炎症的促或抗溶作用的因果机制。 在AIM 1中，其中包括一种可诱导的遗传学方法来阻断关节或药理中的脂肪分解 增强脂解的方法。在第二个目标中，将使用诱导的遗传方法来抑制 巨噬细胞中过氧化物体增殖物激活受体-γ（PPARγ）或刺激PPARγ药物。 第三个目标结合了DMM模型中的物理和PPARγ药物治疗 与单独运动相比，可以改善疼痛和功能的协同互动。通过专注于细胞 和OA运动疗法的分子换能器，拟议的研究测试了新的创新范式 设计药物以潜在OA运动疗法的治疗作用。拟议的研究是 意义重大，因为它将启动有关如何操纵滑膜联合代谢的系统研究 促进关节炎症的分辨率。预计这些知识对其他OA很重要 疗法，例如优化关节环境以支持干细胞和基于组织工程 再生医学策略。