Modulation of local adenosine signaling to attenuate fracture pain

PAGRANT的摘要（调节局部腺苷信号以减轻骨折疼痛 R01AR079189） 骨科骨折引起的疼痛的管理仍然是一个挑战，作为常见的镇痛药物 如非甾体抗炎药（NSAID）和阿片类药物，要么干扰愈合，要么具有 不必要的副作用，如依赖性。考虑到骨科手术引起的疼痛的普遍性 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）作为一种 用于治疗骨折疼痛的治疗剂。ADO是一种天然存在的小分子， 对周围神经和中枢神经的损伤和兴奋性镇痛作用。我们和其他人已经证明， 细胞外ADO是促进骨形成和骨折愈合的有效骨合成代谢剂。的 ADO的骨合成代谢功能沿着镇痛作用使其成为治疗骨折的理想分子 痛苦该提案的总体目标是评估ADO用于治疗疼痛的情况， 通过推进对ADO如何减轻骨折疼痛的基本理解， 开发新的临床可行的治疗策略。为此，将制定提案的目标1， 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- 对骨折愈合的依赖性影响。为了确定生物材料辅助的ADO局部递送是否提供 骨折损伤后的镇痛作用，目标2中的研究将对疼痛、组织 分析，通过开发DRG芯片平台进行体外分析，以及RNA测序。目标3将测试 假设ADO介导的骨折疼痛缓解涉及A1受体（A1Rs）， 条件性敲除感觉神经元A1R，并阐明其对离子通道的调节作用。 该提案的完成将为骨折创伤的护理建立一种新的治疗分子， 可能会改变骨损伤的治疗方式。我们的研究使用局部递送的广泛影响， ADO可以扩展到各种类型的急性和慢性疼痛的管理， 外周或中枢神经系统。

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.