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: 10614931
• 负责人: Shyni Varghese
• 金额: $ 48.23万
• 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/10614931
• 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 作为常用镇痛药物，治疗骨科骨折引起的疼痛仍然是一个挑战 例如非甾体抗炎药 (NSAID) 和阿片类药物会干扰愈合或具有 不良副作用，例如依赖性。鉴于骨科手术相关疼痛的普遍存在 和骨折，迫切需要制定可以减轻疼痛的治疗策略，同时 促进骨折愈合。这促使我们研究腺苷 (ADO) 作为治疗药物的潜在用途 治疗骨折疼痛的药物。 ADO 是一种天然存在的小分子，在受伤时会释放， 对周围和中枢神经产生镇痛作用。我们和其他人已经证明细胞外 ADO 一种有效的骨合成代谢剂，促进骨形成和骨折愈合。骨合成代谢功能 ADO 与镇痛功能使其成为治疗骨折疼痛的理想分子。总体目标是 该提案旨在通过推进 ADO 在骨折损伤疼痛管理中的应用来评估 对 ADO 如何减轻骨折疼痛和开发新的临床可行治疗方法的基本了解 策略。为此，该提案的目标 1 将开发并表征一种可注射生物材料，供当地使用 将 ADO 递送至骨折部位，并确定对骨折愈合的剂量依赖性影响。确定 生物材料辅助 ADO 局部递送是否能在骨折损伤后提供镇痛作用，研究 目标 2 将通过开发 DRG-on-Chip 进行疼痛行为测试、组织分析、体外分析 平台和RNA测序。目标 3 将检验 ADO 介导的骨折疼痛减轻的假设 通过使用在感觉神经元中条件性敲除 A1R 的动物来涉及 A1 受体 (A1R)，以及 阐明了其对离子通道的调节。该提案的完成将建立一种新的治疗分子 用于治疗骨折创伤，并可能改变骨损伤的治疗方式。我们的广泛影响 使用 ADO 局部给药的研究可以扩展到各种类型的急性和慢性疾病的治疗。 起源于周围或中枢神经系统的慢性疼痛。