Modulation of local adenosine signaling to attenuate fracture pain

调节局部腺苷信号传导以减轻骨折疼痛

• 批准号: 10812649
• 负责人: Shyni Varghese
• 金额: $ 7.94万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10812649
• 关键词: 3-Dimensional; Acceleration; Acids; Acute Pain; Address; Adenosine; Adenosine A1 Receptor; Affect; Afferent Neurons; Agonist; Analgesics; Animals; Appearance; Attenuated; Behavior; Biocompatible Materials; Bone Injury; Bone callus; Brain-Derived Neurotrophic Factor; Buprenorphine; Caring; Central Nervous System; Clinical; Cyclic AMP; Data; Dependence; Development; Dinoprostone; Dissociation; Dose; Economic Burden; Environment; Esthesia; Facial Expression; Fracture; Gel; Goals; Harvest; Hyaluronic Acid; In Vitro; Injectable; Injury; Ion Channel; Light; Locomotion; Matrix Metalloproteinases; Mechanics; Mediating; Medical; Membrane Potentials; Microfluidic Microchips; Microfluidics; Mus; Nerve; Neurons; Neuropeptides; Nociceptors; Non-Steroidal Anti-Inflammatory Agents; Opioid; Orthopedic Surgery; Orthopedics; Osteogenesis; Pain; Pain management; Peripheral; Peripheral Nerves; Pharmaceutical Preparations; Prevalence; Production; Purinergic P1 Receptors; Receptor Signaling; Regulation; Role; Sensory Receptors; Series; Signal Transduction; Site; Small Interfering RNA; Stains; Stimulus; TRPV1 gene; Testing; Therapeutic; Therapeutic Agents; Tibial Fractures; Tissues; Trauma; Weight-Bearing state; Work; addiction liability; antagonist; behavior test; bone fracture repair; chronic pain; conditional knockout; crosslink; experimental study; extracellular; gait examination; healing; improved; in vivo; knock-down; neurite growth; neurotrophic factor; novel therapeutic intervention; novel therapeutics; pain reduction; pain relief; pain sensitivity; receptor; receptor expression; scaffold; side effect; skeletal; skeletal tissue; small molecule; success; therapeutically effective; tibia; transcriptome sequencing; transcriptomics

ABSTRACT Management of pain arising from orthopedic fractures remains a challenge as common analgesic medications such as non-steroidal anti-inflammatory drugs (NSAIDs) and opiates either interfere with healing or possess unwanted side effects such as dependence. Given the prevalence of pain associated with orthopedic surgeries and bone fractures, there is an urgent need to develop therapeutic strategies that can mitigate pain while promoting fracture healing. This motivated us to study the potential use of adenosine (ADO) as a therapeutic agent for managing fracture pain. ADO is a naturally occurring small molecule that is released upon injury and elicits analgesic effects in peripheral and central nerves. We and others have shown that extracellular ADO is an effective osteoanabolic agent promoting bone formation and fracture healing. The osteoanabolic function of ADO along with the analgesic function makes it an ideal molecule to treat fracture pain. The overarching goal of the proposal is to assess the use of ADO for the management of pain in fracture injuries by advancing the fundamental understanding of how ADO mitigates fracture pain and developing new clinically viable therapeutic strategies. Towards this, Aim 1 of the proposal will develop and characterize an injectable biomaterial for local delivery of ADO to the fracture site, and determine the dose-dependent effect on fracture healing. To determine whether biomaterial-assisted local delivery of ADO provides analgesic effects following fracture injury, studies in Aim 2 will perform behavioral tests for pain, tissue analyses, in vitro analyses by developing DRG-on-Chip platforms, and RNA sequencing. Aim 3 will test the hypothesis that ADO-mediated fracture pain mitigation involves A1 receptors (A1Rs) by using animals with conditional knockout of A1R in sensory neurons, and elucidates its regulation of ion channels. Completion of this proposal will establish a new therapeutic molecule for the care of fracture trauma, and potentially change how bone injuries are treated. The broad impact of our studies using localized delivery of ADO could be extended to the management of various types of acute and chronic pain that originate in the peripheral or central nervous system.

抽象的 骨科骨折引起的疼痛的管理仍然是一个挑战，因为常见的镇痛药 例如非甾体类抗炎药（NSAID），阿片类药物要么干扰或拥有 不必要的副作用，例如依赖性。鉴于与骨科手术有关的疼痛患病率 和骨折，迫切需要制定可以减轻疼痛的治疗策略 促进断裂愈合。这促使我们研究了腺苷（ADO）作为治疗的潜在用途 管理骨折疼痛的代理。 ADO是一种天然存在的小分子，在受伤后释放 引起周围和中央神经的镇痛作用。我们和其他人已经表明细胞外ADO是 一种有效的骨代谢剂，促进骨形成和断裂愈合。骨拨函数的功能 ADO以及镇痛功能使其成为治疗断裂疼痛的理想分子。总体目标 该提议是通过推进骨折伤害的疼痛的使用来评估ADO的使用 基本了解ADO如何减轻骨折疼痛并发展新的临床可行治疗 策略。为此，提案的目标1将发展并表征当地的注射生物材料 将ADO递送到断裂部位，并确定剂量依赖性对断裂愈合的作用。确定 生物材料辅助ADO的局部递送是否在骨折损伤后会产生镇痛作用，研究 AIM 2将通过开发芯片DRG进行疼痛，组织分析，组织分析的行为测试 平台和RNA测序。 AIM 3将检验Ado介导的减轻骨折疼痛的假设 通过在感觉神经元中使用动物与A1R有条件敲除的动物，涉及A1受体（A1RS），并且 阐明其对离子通道的调节。该建议的完成将建立一个新的治疗分子 为了护理骨折创伤，并有可能改变治疗骨损伤的方式。我们的广泛影响 使用ADO局部交付的研究可以扩展到各种急性的管理 起源于周围或中枢神经系统的慢性疼痛。