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限制 与一般人群相比。OA和当前疼痛没有疾病修饰治疗 药物（例如，阿片类药物和NSAID）具有有限的长期功效和不良副作用。未解决 细胞和分子关节炎症被认为是OA进展的中心机制。然而，在这方面， 该领域进展的障碍是确定慢性OA炎症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如何在分子机制 运动疗法减少OA炎症和疼痛，从而可以鉴定协同药物靶点， 用于治疗用途。这种应用的前提是巨噬细胞依赖于脂质代谢 重新编程以完成抗炎替代激活。这里的目标是确定如何 关节内脂肪组织脂解通过调节抗炎巨噬细胞改变关节炎症 极化中心假设是，关节炎症的解决需要时间耦合， 髌骨下脂肪垫（IFP）脂肪分解与巨噬细胞脂质吸收和脂肪酸代谢，以推动替代方案 activation.这一假设是基于申请人令人兴奋的初步数据而提出的，这些数据表明， 运动触发膝关节滑膜中促炎细胞因子和巨噬细胞的短暂诱导 和IFP，它完全解决了第14天的运行。值得注意的是，炎症的诱导和消退发生在 与IFP脂解、纤维化和脂肪生成短暂循环并行。建议的理由 研究的重点是了解关节组织代谢物和细胞代谢物之间的因果关系， 炎症介质有可能通过推进基础治疗来创造新的治疗机会 了解关节炎症是如何调节的。凭借强大的初步数据和专业知识， 动物运动、代谢和OA研究，申请人将通过追求三个具体的 目的：1）确定关节内脂肪组织脂解如何介导巨噬细胞活化，关节 炎症和创伤后OA; 2）确定巨噬细胞脂质摄取和脂肪酸的影响 氧化对关节炎症和创伤后OA的发展;和3）开发一种组合的 针对脂质代谢的物理和生物干预策略，以减少关节炎症和疼痛， 慢性膝关节OA的临床前模型。目的1和2将在消退和非消退的小鼠模型中进行测试。 使用车轮运行和内侧半月板（DMM）模型的不稳定来解决关节炎症， 分别这些模型在申请人手中已经建立为可行的，将用于测试 确定关节内脂质对关节炎症的促进或抑制消退作用的因果机制。 在目标1中，这些包括一种可诱导的遗传方法来阻断关节中的脂解或药理学方法。 方法来增强脂肪分解。在第二个目标中，将使用诱导遗传方法来抑制 过氧化物酶体增殖物激活受体-γ（PPARγ）在巨噬细胞或刺激PPARγ。 第三个目的是在DMM模型中结合物理和PPARγ药物治疗，以测试 协同作用，改善疼痛和功能比单独锻炼。通过关注细胞 和分子换能器的OA运动疗法，拟议的研究测试新的，创新的范例， 设计药物以增强OA运动疗法的治疗效果。拟议的研究是 意义重大，因为它将启动如何操纵滑膜关节代谢的系统研究， 促进关节炎的消退。这方面的知识预计也将是重要的其他OA 治疗，例如优化关节环境以支持基于干细胞和组织工程的 再生医学战略。