Epigenetic Determinants Influencing Development and Evolution of Chronic Post-surgical Pain in Children Undergoing Musculoskeletal Surgery.

表观遗传决定因素影响接受肌肉骨骼手术的儿童慢性术后疼痛的发展和演变。

• 批准号: 10676771
• 负责人: Vidya Chidambaran
• 金额: $ 65.38万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676771
• 关键词: Adolescent; Adult; Affect; Age; Binding; Bioinformatics; Biological Assay; Biological Markers; Blood; Blood Cells; Blood specimen; Brain; Cells; Child; Child Rearing; Chromatin; Chronic; Congenital funnel chest; Cyclic AMP; DNA Methylation; Data; Defect; Development; Dopamine; Drug abuse; Emotional; Environmental Risk Factor; Epigenetic Process; Etiology; Event; Evolution; Exposure to; Feedback; Fostering; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genetic Variation; Genomic Segment; Goals; Heredity; Histones; Immune; Immune signaling; Immune system; Impairment; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Longitudinal Studies; Measures; Mediating; Mental disorders; Methylation; Mission; Modification; Musculoskeletal; Operative Surgical Procedures; Opioid; Opioid Analgesics; Pain; Pain management; Parent-Child Relations; Pathway interactions; Patients; Perioperative; Persistent pain; Pharmaceutical Preparations; Phenotype; Positioning Attribute; Postoperative Pain; Predisposition; Preventive; Process; Promoter Regions; Psychosocial Factor; Public Health; Quality of life; Race; Receptor Gene; Recovery; Reporting; Research; Risk; Role; Signal Pathway; Site; Socioeconomic Status; Spinal Fusion; Spine surgery; Stress; T-Lymphocyte Subsets; Targeted Research; Testing; Therapeutic; Tissues; Twin Studies; United States National Institutes of Health; Validation; Vertebral column; addiction; brain cell; candidate marker; chemical stability; chronic pain; chronic painful condition; clinical decision support; cohort; comparison control; cytokine; disability risk; disease phenotype; epigenetic marker; epigenetic regulation; epigenetic variation; epigenome-wide association studies; functional disability; gamma-Aminobutyric Acid; immunoregulation; improved; innovation; insight; inter-individual variation; methylation biomarker; monocyte; mu opioid receptors; multidisciplinary; neural; novel; nutrition; opioid abuse; opioid exposure; opioid use; pain chronification; pain patient; pain processing; patient oriented research; personalized medicine; potential biomarker; prescription opioid abuse; prevent; promoter; prospective; psychosocial; repaired; response; risk prediction; risk stratification; scoliosis; sex; stressor; therapeutic target; transcription factor; translational impact

PROJECT SUMMARY Spine fusion and pectus repair are among the most painful musculoskeletal surgeries adolescents undergo, with a high incidence of chronic postsurgical pain (CPSP). CPSP is detrimental to recovery and increases the risk for disability as well as prescription opioid abuse. Understanding CPSP risk is important for development of effective preventive and therapeutic strategies. Although genetic, psychosocial and environmental factors explain some of the variance in CPSP risk, there remain critical gaps in CPSP risk prediction and understanding of longitudinal gene-environmental influences on long-term pain responses after surgery. This leads us to our global hypothesis that epigenetic processes will influence the development and evolution of CPSP. DNA methylation (DNAm) is a key epigenetic mechanism known to influence transcription and transition of acute to chronic pain. Preliminary data: Our pilot epigenome-wide association study (EWAS) in spine surgical subjects showed that CPSP is associated with differential DNAm in 39 genes which enrich GABA, Dopamine-DARPP32 Feedback in cAMP and immune signaling pathways. Our previous findings that DNAm of Mu opioid receptor gene promoter, perioperative pain and opioid exposures predict CPSP, lead us to believe that DNAm mediates the association of perioperative stressors with long-term pain phenotypes. Increased cytokine levels and DNAm-expression correlations in CPSP (pilot data) suggest differential epigenetic regulation influencing immune cell-specific gene expression in CPSP. Scientific objectives are to determine blood DNAm biomarkers for CPSP and evaluate temporal origins of CPSP-associated epigenetic variation in relation to pain-opioid exposures and inflammatory responses. The premise for the potential utility of blood based DNAm as CPSP biomarkers is supported by cross tissue comparison studies of brain-blood DNAm correlations and blood DNAm signatures reported for several neural phenotypes. Aim 1: Determine and validate differentially methylated regions predictive of CPSP. The working hypothesis is that CPSP will be significantly associated with DNAm markers in preoperative blood samples after adjusting for demographic, psychosocial and perioperative factors. We will conduct a prospective, multisite EWAS for discovery-validation (N=1165 opioid-naïve children undergoing spine fusion) and replication of candidate markers (N=300 children undergoing pectus repair). Since cross-sectional epigenetic studies are potentially affected by reverse causation bias and genetic variation confounders, we propose novel longitudinal studies to evaluate perioperative stress related DNAm changes. Aim 2: Determine longitudinal changes in DNAm profiles associated with pain and opioid exposures and explore their role in mediating associations with CPSP. Aim 3: Characterize cytokine profiles, immune cell subsets and epigenetic regulation of immune cell specific gene expression in CPSP. It is anticipated that this study will identify novel epigenetic biomarkers for CPSP, provide novel insights into longitudinal epigenetic mechanisms in the evolution of CPSP, and uncover promising therapeutic targets for CPSP, with extended implications for other chronic pain conditions.

项目概要 脊柱融合和胸胸修复是青少年接受的最痛苦的肌肉骨骼手术之一， 慢性术后疼痛 (CPSP) 的发生率较高，会导致恢复过程中出现疼痛，并增加术后风险。 了解 CPSP 风险对于提高有效性非常重要。 尽管遗传、心理、社会和环境因素可以解释一些。 尽管 CPSP 风险的方差不同，但 CPSP 风险预测和纵向理解仍存在重大差距 基因环境对手术后长期疼痛反应的影响这使我们了解了我们的全球情况。 假设表观遗传过程会影响 CPSP DNA 甲基化的发展和进化。 (DNAm) 是一种关键的表观遗传机制，已知会影响急性疼痛向慢性疼痛的转录和转变。 初步数据：我们在脊柱外科受试者中进行的试点全表观基因组关联研究 (EWAS) 表明 CPSP 与 39 个基因中的差异 DNAm 相关，这些基因丰富了 GABA、多巴胺-DARPP32 我们之前的研究发现 Mu 阿片受体基因启动子的 DNAm， 围手术期疼痛和阿片类药物暴露可预测 CPSP，使我们相信 DNAm 介导这种关联 具有长期疼痛表型的围手术期应激源的细胞因子水平和 DNAm 表达增加。 CPSP（试点数据）中的相关性表明影响免疫细胞特异性基因的差异表观遗传调控 科学目标是确定 CPSP 的血液 DNAm 生物标志物并评估 与疼痛阿片类药物暴露和炎症相关的 CPSP 相关表观遗传变异的时间起源 基于血液的 DNAm 作为 CPSP 生物标志物的潜在用途的前提得到了支持。 脑-血液 DNAm 相关性和血液 DNAm 特征的跨组织比较研究报告 目标 1：确定并验证预测 CPSP 的差异甲基化区域。 工作假设是 CPSP 将与术前血液中的 DNAm 标记显着相关 在调整人口、心理社会和围手术期因素后，我们将进行前瞻性、 用于发现验证的多站点 EWAS（N=1165 名未使用阿片类药物且接受脊柱融合的儿童）和复制 候选标记（N=300 名接受胸肌修复的儿童）。 可能受到反向因果偏差和遗传变异混杂因素的影响，我们提出了新的纵向 研究评估围手术期应激相关的 DNAm 变化。目标 2：确定 DNAm 的纵向变化。 DNAm 谱与疼痛和阿片类药物暴露相关，并探讨它们在介导与疼痛和阿片类药物的关联中的作用 CPSP 目标 3：表征细胞因子谱、免疫细胞亚群和免疫细胞的表观遗传调控。 预计这项研究将鉴定出 CPSP 中的新表观遗传生物标志物。 CPSP，为 CPSP 进化中的纵向表观遗传机制提供新见解，并揭示 CPSP 有希望的治疗目标，对其他慢性疼痛疾病具有广泛的影响。

项目成果

Current Evidence for Biological Biomarkers and Mechanisms Underlying Acute to Chronic Pain Transition across the Pediatric Age Spectrum.

• DOI: 10.3390/jcm12165176
• 发表时间: 2023-08-09
• 期刊: Journal of clinical medicine
• 影响因子: 3.9

The Role of Cytokines in Acute and Chronic Postsurgical Pain in Pediatric Patients after Major Musculoskeletal Surgeries.

细胞因子在重大肌肉骨骼手术后儿童患者急性和慢性术后疼痛中的作用。

• DOI: 10.1101/2024.03.27.24304974
• 发表时间: 2024
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Chidambaran,Vidya;Duan,Qing;Pilipenko,Valentina;Glynn,SusanM;Sproles,Alyssa;Martin,LisaJ;Lacagnina,MichaelJ;King,ChristopherD;Ding,Lili
• 通讯作者: Ding,Lili