Pediatric Persistent Post-surgical Pain: From Animals to Application

项目总结/摘要 儿科慢性疼痛是一个严重的公共卫生问题，导致高水平的医疗保健利用， 残疾。与慢性疼痛相关的生理和心理后果影响整体健康 并且可使成人慢性疼痛的发展更易发生。具体来说， 对小儿术后持续性疼痛（PPP）进行的研究，鉴于以下情况， 每年有超过500万儿童接受手术，25%的成年人在慢性疼痛诊所接受手术， 手术作为前提。拟议的转化研究项目利用动物模型，人类， 遗传学和心理生理学技术来增强我们对这些机制的理解。很长的- 这个K23奖的长期目标是为候选人建立一个独立的翻译研究生涯 旨在开发基于机制的行为干预。拟议项目的目的是 开发一种动物模型，探索基因-环境相互作用、年龄和生物性别如何影响 手术前后的疼痛阈值，这将作为第一步，功能分析遗传 我们希望在人类研究的基因关联臂中发现这些机制。这个人的手臂 项目是双重的;研究儿童压力和遗传疼痛风险对当前疼痛和功能的作用 在一个大型的成年手术患者队列中，以及继续进行IRB批准的研究，检查感觉， 儿童PPP和相关功能障碍的心理社会和遗传预测因子， 接受脊柱融合手术的特发性脊柱侧凸或接受髋关节置换术的髋关节发育不良 截骨术选择该人群作为模型条件，因为这些是骨科条件 影响儿童，儿童在其他方面是健康的，这两种手术都是相当侵入性和复杂的， 我们的研究表明，这些患者中有很大一部分会发展为中度至重度疼痛， 手术后。主要的培训目标是获得疼痛遗传学，动物模型， 翻译研究候选人将通过以下方式实现这一目标：1）在临床/研究中的指导 环境，2）由候选人的赞助商和共同赞助商进行动物模型和遗传学方面的实践培训 辅之以遗传学和高级统计学的教学法，以及3）执行拟议的研究 计划这些研究将为R 01的开发提供必要的数据， 表观遗传模型，以确定研究基因，这显着改变PPP的风险概况，并将告知 为高危人群开发新的药物靶点和行为干预。

Project Summary/Abstract Pediatric chronic pain is a serious public health problem resulting in high levels of healthcare utilization and disability. The physical and psychological consequences associated with chronic pain impact overall health and can predispose the development of adult chronic pain. Specifically, there has been an inadequate amount of research conducted on pediatric persistent postsurgical pain (PPP), which is urgently required given that over 5 million children undergo surgery each year and 25% of adults presenting to chronic pain clinics identify surgery as the antecedent. The proposed translational research project utilizes animal models, humans, genetics, and psychophysiological techniques to enhance our understanding of these mechanisms. The long- term goal of this K23 award is for the candidate to establish an independent translational research career aimed at developing mechanistically based behavioral interventions. The intent of the proposed project is to develop an animal model exploring how gene-environmental interactions, age, and biological sex contribute to pre- and post surgical pain thresholds, which will serve as a first step to functionally assaying genetic mechanisms we hope to discover in the gene association arm of our human studies. The human arm of this project is two-fold; examining the role of childhood stress and genetic pain risk on current pain and functioning in a large cohort of adult surgical patients, as well as continuing an IRB-approved study examining the sensory, psychosocial, and genetic predictors of PPP and related functional disability in pediatric patients with either idiopathic scoliosis undergoing spinal fusion surgery or developmental dysplasia of the hip undergoing hip osteotomy. This population was selected as a model condition because these are orthopedic conditions affecting children, the children are otherwise healthy, and both surgeries are quite invasive and complex with our research indicating that that a high proportion of these patients go onto to develop moderate to severe pain after surgery. The primary training objective is to acquire expertise in pain genetics, animal models, and translational research. The candidate will accomplish this through: 1) mentorship in a clinical/research environment, 2) hands-on training in animal models and genetics by the candidate's sponsor and co-sponsors complemented by didactics in genetics and advanced statistics, and 3) execution of the proposed research plan. These studies will provide the necessary data to inform the development of an R01 to focus on an epigenetic model to identify study genes, which markedly alter the risk profile for PPP and which will inform the development of new drug targets and behavioral interventions for those at greatest risk.