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: 10543700
• 负责人: Shyni Varghese
• 金额: $ 6.62万
• 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/10543700
• 关键词: 3-Dimensional; 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; Clinical; Cyclic AMP; Data; Dependence; Development; Dinoprostone; Dose; Economic Burden; Environment; Esthesia; Facial Expression; Fracture; Goals; Harvest; Hyaluronic Acid; In Vitro; Injectable; Injury; Ion Channel; Light; Locomotion; Matrix Metalloproteinases; Mechanics; Mediating; Medical; Membrane Potentials; Microfluidic Microchips; Microfluidics; Mus; Nerve; Neuraxis; 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; RNA analysis; 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; base; 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; parent grant; receptor; receptor expression; scaffold; side effect; skeletal; skeletal tissue; small molecule; success; therapeutically effective; tibia; transcriptome sequencing; transcriptomics

ABSTRACT OF PARENT GRANT (Modulation of local adenosine signaling to attenuate fracture pain R01AR079189) 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.

Parent Grant摘要(调节局部腺苷信号以减轻骨折疼痛 R01AR079189) 作为常见的止痛药，骨科骨折引起的疼痛的处理仍然是一个挑战 例如非类固醇抗炎药(NSAIDs)和阿片类药物干扰愈合或具有 不想要的副作用，如依赖性。鉴于与整形外科手术相关的疼痛盛行 和骨折，迫切需要开发能够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)作为一种 治疗骨折疼痛的治疗剂。ADO是一种自然产生的小分子，它被释放出来 在受伤时，并在外周和中枢神经引起止痛效果。我们和其他人已经证明了 细胞外ADO是一种有效的促进骨形成和骨折愈合的骨合成代谢剂。这个 ADO的骨合成代谢功能和镇痛功能使其成为治疗骨折的理想分子 疼痛。该提案的总体目标是评估ADO在疼痛管理中的使用 通过促进对ADO如何缓解骨折疼痛和 开发新的临床可行的治疗策略。为此，提案的目标1将发展和 确定用于将ADO局部输送到骨折部位的可注射生物材料的特征，并确定剂量- 对骨折愈合的依赖作用。为了确定生物材料辅助的ADO局部递送是否提供 骨折损伤后的止痛效果，AIM 2中的研究将对疼痛、组织进行行为测试 分析，通过开发DRG-on-Chip平台进行体外分析，以及RNA测序。AIM 3将测试 ADO介导的骨折疼痛缓解涉及A1受体(A1Rs)的动物假说 A1R的条件性敲除，并阐明其对离子通道的调节。 这项提议的完成将建立一个新的治疗分子，用于治疗骨折创伤，以及 可能会改变骨骼损伤的治疗方式。我们的研究使用本地化交付的广泛影响 ADO可以扩展到治疗各种类型的急性和慢性疼痛，这些疼痛起源于 外周或中枢神经系统。