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.

项目总结

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