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: 9780367
• 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/9780367
• 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; Lead; Lipids; Lipolysis; 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 alpha; PPAR gamma; Pain; Pain management; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phenotype; Physical therapy; Physical therapy exercises; 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; Veterans; base; cytokine; disability; engineered stem cells; exercise intervention; fatty acid metabolism; fatty acid oxidation; functional outcomes; gait examination; genetic approach; improved; improved outcome; in vivo; in vivo evaluation; innovation; instrument; joint inflammation; lipid biosynthesis; lipid metabolism; macrophage; mechanical allodynia; meniscus injury; mouse genetics; mouse model; nanoparticle; novel strategies; novel therapeutics; osteoarthritis pain; physically handicapped; prevent; response; rosiglitazone; side effect; tissue-repair responses; treadmill; treatment strategy; 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) 对退伍军人的影响尤为严重，导致更多的疼痛和功能限制 与一般人群相比，目前尚无针对 OA 和疼痛的疾病缓解疗法。 药物（例如阿片类药物和非甾体抗炎药）的长期疗效有限且不良副作用尚未解决。 细胞和分子关节炎症被认为是 OA 进展的核心机制。 该领域取得进展的一个障碍是确定慢性骨关节炎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实现这一目标的分子机制。 运动疗法可减少 OA 炎症和疼痛，从而可以确定协同药物靶点并 开发用于治疗用途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。 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 中心假设是关节炎症的解决需要时间耦合。 髌下脂肪垫 (IFP) 脂肪分解与巨噬细胞脂质摄取和脂肪酸代谢驱动替代 该假设是基于申请人令人兴奋的初步数据而提出的，该数据表明： 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，在跑步第 14 天完全消退 值得注意的是，炎症发生了诱导和消退。 与 IFP 脂肪分解、纤维化和脂肪生成的瞬时循环并行。 研究的目的是了解关节组织代谢物与细胞之间的因果关系 炎症介质有可能通过促进基础治疗产生新的治疗机会 关于如何调节关节炎症的知识，具有强大的初步数据和专业知识。 动物运动、新陈代谢和 OA 研究，申请人将通过追求三个具体的假设来检验假设 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 发展的影响；3) 开发联合疗法； 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 目标 1 和 2 将在缓解型和非缓解型小鼠模型中测试慢性膝 OA 的临床前模型。 使用车轮运行和内侧半月板 (DMM) 模型不稳定来解决关节炎症， 申请人手中已建立的可行模型将分别用于测试。 建立关节内脂质对关节炎症的促进或抗消退作用的因果机制。 在目标 1 中，这些措施包括阻止关节脂肪分解的诱导遗传方法或药物 增强脂肪分解的方法在第二个目标中，将使用诱导遗传方法来抑制。 巨噬细胞中的过氧化物酶体增殖物激活受体-γ (PPARγ) 或在药理学上刺激 PPARγ。 第三个目标在 DMM 模型中结合物理治疗和 PPARγ 药物治疗，以测试 通过关注细胞，协同相互作用比单独运动更能改善疼痛和功能。 和 OA 运动疗法的分子传感器，拟议的研究测试了新的创新范式 设计药物来增强 OA 运动疗法的治疗效果。 意义重大，因为它将启动关于如何操纵滑膜关节代谢的系统研究 促进关节炎症的解决，预计这一知识对于其他 OA 也很重要。 疗法，例如优化关节环境以支持干细胞和基于组织工程的 再生医学策略。