"Novel therapeutic approaches to improve fracture healing while reducing pain behavior"

“改善骨折愈合同时减少疼痛行为的新治疗方法”

• 批准号: 10609035
• 负责人: Melissa A Kacena
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609035
• 关键词: AVIL gene; Abdomen; Acute Pain; Afferent Neurons; Age; Analgesics; Animals; Aspartic Acid; Autologous Transplantation; BMP2 gene; Biological; Biosensor; Bone Marrow; Bone Morphogenetic Proteins; Bone Pain; Bone Regeneration; Bone callus; CASP1 gene; Cell Lineage; Cells; Cervical; Chest; Conditioned Culture Media; Data; Defect; Drug usage; FDA approved; Femur; Forelimb; Fracture; Genes; Growth; Harvest; Health; Healthcare Systems; Hindlimb; Hip region structure; Histone Deacetylase; Image; Impaired cognition; Impairment; Implant; In Vitro; Inflammasome; Inflammation; Inflammatory; Injury; Limb Bud; Lower Extremity; Mechanics; Mediating; Mesenchymal; Mesenchyme; Messenger RNA; Monitor; Mus; Nerve Degeneration; Nervous System; Neurites; Neuropathy; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Opioid; Orthopedics; PPAR gamma; Pain; Pain Measurement; Pain management; Pathway interactions; Patient-Focused Outcomes; Patients; Peripheral; Pharmaceutical Preparations; Phenotype; Postoperative Pain; Postoperative Period; Prevention; Process; Proliferating; Property; Proteins; Recovery; SIRT1 gene; Site; Spinal Fusion; Spinal Ganglia; Stimulus; Stromal Cells; Surgeon; TP53 gene; Techniques; Testing; Tissues; Titrations; Transgenic Mice; Trauma; Veterans; Work; addiction; bone; bone fracture repair; bone healing; bone loss; bone repair; cancer risk; cell growth; chronic pain; cytokine; disability; fighting; healing; improved; in vivo; in vivo imaging system; inflammatory marker; injured; limb injury; novel; novel therapeutic intervention; novel therapeutics; opioid epidemic; pain behavior; pain reduction; paracrine; pharmacologic; promoter; side effect; skeletal; skeletal injury; spatiotemporal; surgical pain; transcriptome sequencing

Veterans with fractures suffer from injury-associated pain as well as post-operative surgical pain. The occurrence of a fracture contributes to acute pain and is largely manifested by mechanical, inflammatory, and neuropathic components. The LEAP study of high-energy lower extremity trauma showed that acute pain, in the recovery period after severe trauma, is the single largest predictor of long-term chronic pain 5-10 years after injury. There are 2 main strategies to treat trauma-induced and post-surgical pain: opioids and nonsteroidal anti-inflammatory drugs (NSAIDs). Neither drug class completely alleviates pain, and both have negative side effects. Opioids, beyond eliciting cognitive impairment, are commonly associated with tolerance and addiction. NSAIDs are commonly used in combination with opioids following thoracic/abdominal surgery but use of this drug class for fracture pain is discouraged in the U.S. due to negative effects on skeletal health and healing of the injured skeleton. It is unclear which drug class is less destructive to the bone repair process but prevention of nonunion is paramount in the treatment of fractures as it places additional burden on the patient and the healthcare system due to prolonged pain and disability. Therefore, identification of therapies which improve both the bone healing process and diminish the fracture-associated pain is warranted. Our recent data demonstrate that mRNA levels of Sirtuin-1 (Sirt1, an NAD+ class III histone deacetylase) are robustly elevated during fracture healing. Fracture healing is impaired with age, bone loss, inflammation, and with neurodegeneration. Importantly, Sirt1 improves all of these conditions; however, to our knowledge, with the exception of our studies, nobody has specifically examined the effects of Sirt1 on fracture repair. Here we show that pharmacological activation of Sirt1 by SRT1720 allows for improved fracture healing while reducing pain behaviors. Based on these observations we hypothesize that activation of Sirt1 in mesenchymal lineage cells and associated nervous system interactions will enhance bone healing and reduce pain in mice by regulating inflammation. The proposed work will test this hypothesis, and may provide evidence that pharmacologic activation of Sirt1 could serve both as a novel bone healing agent and post-fracture analgesic agent. In Aim 1, we will demonstrate that SRT1720 can improve bone healing and reduce pain behaviors and inflammation in mice, and determine which cells require Sirt1 activation by SRT1720 for successful bone healing, reduced pain behaviors, and reduced inflammation. In Aim 2, we will determine how SRT1720 treatment, mesenchymal lineage cells, and primary afferent sensory neurons (PANs) regulate inflammation, and we will examine the crosstalk between mesenchymal lineage cells and PANs. Successful accomplishment of these Aims will demonstrate the utility of using Sirt1 activators as novel bone healing and post-fracture analgesic agents. The latter, could replace the necessity of opioids for pain management, serve as an important step in fighting the opioid crisis, and could significantly improve patient outcomes.

患有骨折的退伍军人会遭受受伤相关的疼痛以及手术后的疼痛。这 骨折的发生会导致急性疼痛，主要表现为机械性、炎症性和 神经病理性成分。高能量下肢创伤的 LEAP 研究表明，急性疼痛 严重创伤后的恢复期是 5-10 年长期慢性疼痛的最大预测因素 受伤后。治疗创伤引起的疼痛和手术后疼痛有两种主要策略：阿片类药物和 非甾体类抗炎药（NSAID）。这两种药物都不能完全缓解疼痛，并且都具有 负面影响。阿片类药物除了引起认知障碍外，通常还与耐受性相关 和成瘾。非甾体抗炎药通常在胸腹部手术后与阿片类药物联合使用 但由于对骨骼健康的负面影响，在美国不鼓励使用此类药物来治疗骨折疼痛 以及受伤骨骼的愈合。目前尚不清楚哪种药物对骨修复过程的破坏性较小 但预防骨不连在骨折治疗中至关重要，因为它会给骨折带来额外的负担 患者和医疗保健系统因长期疼痛和残疾而受到影响。因此，治疗方法的确定 这既可以改善骨骼愈合过程，又可以减轻骨折相关的疼痛。我们的 最近的数据表明 Sirtuin-1（Sirt1，一种 NAD+ III 类组蛋白脱乙酰酶）的 mRNA 水平 骨折愈合过程中明显升高。骨折愈合会因年龄、骨质流失、炎症和 伴有神经退行性变。重要的是，Sirt1 改善了所有这些状况；然而，据我们所知，随着 除了我们的研究之外，没有人专门研究 Sirt1 对骨折修复的影响。在这里我们 表明 SRT1720 对 Sirt1 的药理学激活可以改善骨折愈合，同时减少 疼痛行为。基于这些观察，我们假设间充质细胞中 Sirt1 的激活 谱系细胞和相关神经系统的相互作用将增强骨骼愈合并减轻疼痛 小鼠通过调节炎症。拟议的工作将检验这一假设，并可能提供证据表明 Sirt1 的药理激活既可以作为新型骨愈合剂，也可以作为骨折后镇痛剂 代理人。在目标 1 中，我们将证明 SRT1720 可以改善骨骼愈合并减少疼痛行为和 小鼠炎症，并确定哪些细胞需要 SRT1720 激活 Sirt1 才能成功成骨 愈合、减少疼痛行为和减少炎症。在目标 2 中，我们将确定 SRT1720 如何 治疗、间充质谱系细胞和初级传入感觉神经元（PAN）调节炎症， 我们将检查间充质谱系细胞和 PAN 之间的串扰。成功的成就 这些目标中的一部分将展示使用 Sirt1 激活剂作为新型骨愈合和骨折后治疗的效用 镇痛剂。后者可以取代阿片类药物用于疼痛管理的必要性，作为一种 对抗阿片类药物危机的重要一步，可以显着改善患者的治疗效果。