Pediatric Persistent Post-surgical Pain: From Animals to Application

项目摘要/摘要 儿科慢性疼痛是一个严重的公共卫生问题，导致医疗保健利用率和 残疾。与慢性疼痛相关的生理和心理后果影响整体健康 并可促进成人慢性疼痛的发展。具体地说，一直有不足的数额。 对儿童手术后持续性疼痛(PPP)进行的研究，这是迫切需要的，因为 每年有500多万儿童接受手术，25%到慢性疼痛诊所就诊的成年人认为 以外科手术为前奏。拟议的翻译研究项目利用动物模型、人类、 遗传学和心理生理学技术，以加强我们对这些机制的理解。长的- 这个K23奖项的学期目标是让候选人建立独立的翻译研究生涯 旨在开发基于机械的行为干预。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、年龄和生物性别对 手术前后的痛阈值，这将是从功能上分析基因的第一步 我们希望在人类研究的基因关联方面发现这些机制。这是人类的手臂 该项目是双重的；研究儿童压力和遗传疼痛风险对当前疼痛和功能的作用 在一大群成年外科患者中，以及继续进行IRB批准的检查感官的研究， PPP和相关功能障碍的儿科患者的心理社会和遗传预测因素 特发性脊柱侧凸脊柱融合术或发育性髋关节发育不良 截骨术。这一人群被选为模型条件，因为这些是骨科条件 在影响儿童的情况下，儿童在其他方面都是健康的，这两种手术都是相当有侵入性的，而且很复杂 我们的研究表明，这些患者中有很大一部分会出现中度到重度的疼痛 手术后。主要的培训目标是获得疼痛遗传学、动物模型和 翻译研究。应聘者将通过以下方式实现这一点：1)临床/研究指导 环境，2)由候选人的赞助商和共同赞助商提供动物模型和遗传学方面的实践培训 辅以遗传学和高级统计学的教学，以及3)执行拟议的研究 计划。这些研究将提供必要的数据，为R01的开发提供信息，以专注于 表观遗传学模型，以确定研究基因，这显著改变了PPP的风险概况，并将 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.