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

基本信息

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
项目类别：
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

项目摘要

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.

家长资助摘要（调节局部腺苷信号传导以减轻骨折疼痛 R01AR079189) 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，迫切需要开发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）作为药物的潜在用途。用于控制骨折疼痛的治疗剂。 ADO 是一种天然存在的小分子，会释放损伤后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 是一种有效的骨合成代谢剂，可促进骨形成和骨折愈合。这 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 在疼痛管理中的应用通过增进对 ADO 如何减轻骨折疼痛和骨折损伤的基本了解开发新的临床可行的治疗策略。为此，该提案的目标 1 将制定并表征用于将 ADO 局部递送至骨折部位的可注射生物材料，并确定剂量骨折愈合的依赖性影响。确定生物材料辅助的 ADO 局部递送是否提供骨折损伤后的镇痛效果，目标 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。目标 3 将进行测试 ADO 介导的骨折疼痛缓解涉及 A1 受体 (A1R) 的假设，通过使用动物条件性敲除感觉神经元中的 A1R，并阐明其对离子通道的调节。该提案的完成将为骨折创伤的治疗建立一种新的治疗分子，并且可能会改变骨损伤的治疗方式。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，这些疼痛源自于周围或中枢神经系统。