"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: 10426446
• 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/10426446
• 关键词: AVIL gene; Abdomen; Acute Pain; Afferent Neurons; 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; Cell Proliferation; Cells; Cervical; Chest; Conditioned Culture Media; Data; Defect; Drug usage; FDA approved; Forelimb; Fracture; Genes; Gold; Growth; HDAC9 gene; 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 structure; Neurites; Neuropathy; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Opioid; Orthopedics; PPAR gamma; Pain; Pain management; Pathway interactions; Patient-Focused Outcomes; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Phenotype; Postoperative Pain; Postoperative Period; Prevention; Process; Property; Proteins; Recovery; SIRT1 gene; Site; Skeleton; Spinal Fusion; Spinal Ganglia; Stimulus; Stromal Cells; Surgeon; TP53 gene; Techniques; Testing; Tissues; Transgenic Mice; Trauma; Veterans; Work; addiction; base; bone; bone aging; bone fracture repair; bone healing; bone loss; bone repair; cancer risk; cell growth; chronic pain; chronic painful condition; 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; promoter; side effect; skeletal; 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遭受与受伤相关的疼痛以及手术后的疼痛。这个 骨折的发生会导致急性疼痛，主要表现为机械性、炎症性和 神经病变成分。高能下肢创伤的LEAP研究表明，急性疼痛，在 严重创伤后的恢复期是5-10年长期慢性疼痛的最大单一预测因素。 受伤后。治疗创伤引起的和手术后疼痛有两种主要策略：阿片类药物和 非甾体抗炎药。两种药物都不能完全缓解疼痛，而且两者都有 副作用很大。阿片类药物，除了引起认知障碍外，通常与耐受性有关 还有毒瘾。胸腹部手术后非类固醇抗炎药常与阿片类药物联合使用 但在美国，由于对骨骼健康的负面影响，不鼓励使用这种药物来治疗骨折疼痛 以及修复受伤的骨骼。目前还不清楚哪一类药物对骨骼修复过程的破坏性较小 但在骨折的治疗中，预防骨不连是最重要的，因为它给骨折患者带来了额外的负担 由于长期疼痛和残疾，患者和医疗保健系统。因此，对疗法的识别 这既能改善骨骼愈合过程，又能减轻骨折相关的疼痛，这是必要的。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水平是 在骨折愈合过程中强劲地升高。骨折愈合因年龄、骨丢失、炎症和 神经退行性变。重要的是，Sirt1改善了所有这些条件；然而，据我们所知，使用 除我们的研究外，还没有人专门研究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，我们推测Sirt1在间充质中的激活 谱系细胞和相关神经系统的相互作用将促进骨愈合和减轻疼痛 通过调节炎症对小鼠的影响。这项拟议的工作将检验这一假设，并可能提供证据 Sirt1的药理活性可作为一种新型的骨愈合剂和骨折后止痛剂 探员。在目标1中，我们将证明SRT1720可以促进骨愈合和减少疼痛行为，并 小鼠的炎症反应，并确定哪些细胞需要SRT1720激活Sirt1才能成功成骨 治愈，减少疼痛行为，减少炎症。在目标2中，我们将确定SRT1720如何 治疗、间充质系细胞和初级传入感觉神经元(PAN)调节炎症， 我们将研究间充质系细胞和PAN之间的串扰。成功的成就 这些目标中将展示使用Sirt1激活剂作为新的骨愈合和骨折后的效用 止痛剂。后者可以取代阿片类药物用于疼痛治疗的必要性，作为一种 这是抗击阿片类药物危机的重要一步，可以显著改善患者的预后。