Transcriptomics of Pain in Sickle Cell Disease

镰状细胞病疼痛的转录组学

• 批准号: 10641957
• 负责人: Vivien Andrea Sheehan
• 金额: $ 38.17万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641957
• 关键词: ATAC-seq; Acceleration; Acute Pain; Address; Adhesions; Adult; Affect; American; Biological Markers; Blood Cells; Caring; Cells; Childhood; Chronic; Collecting Cell; Collection; Confusion; Data; Development; Drug Targeting; Endothelium; Erythrocytes; Erythroid; Erythroid Cells; Etiology; Event; Exhibits; Exposure to; Frequencies; Genes; Genetic Transcription; Genome; Genomics; Germ-Line Mutation; Goals; Hemolytic Anemia; Hospitalization; Hospitals; Hyperalgesia; Impairment; Individual; Inherited; Injury; Ischemia; Leukocytes; Link; Nature; Nociception; Opioid; PTPRC gene; Pain; Pain Measurement; Pain Nature; Pathway interactions; Patients; Phenotype; Predisposition; Provider; Publishing; Quality of life; RNA; Recording of previous events; Resolution; Risk; Risk Factors; Sampling; Sickle Cell Anemia; Somatic Mutation; TFRC gene; Testing; Variant; Work; acute care; biomarker validation; candidate identification; cell type; chronic pain; chronic pain management; chronic pain patient; clinical pain; clinically relevant; cohort; diagnostic biomarker; differential expression; endogenous opioids; experience; genetic variant; genome sequencing; genomic data; genomic variation; improved; individual variation; innovation; longitudinal analysis; metabolomics; methylomics; multiple omics; novel therapeutics; opioid overuse; pediatric patients; precision medicine; prevent; risk prediction; sickling; targeted treatment; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics; vaso-occlusive crisis; whole genome

PROJECT SUMMARY/ABSTRACT Patients with sickle cell disease (SCD) exhibit marked inter-individual heterogeneity in frequency of acute pain events, or vaso-occlusive crises (VOC) and development of chronic pain. The nidus of a VOC is typically the adhesion of a leukocyte to the endothelium, bringing with it a red cell which deoxygenates and sickles, resulting in vaso-occlusion, ischemia, and pain. We therefore collected SCD patient RNA from CD71+ cells (red cell precursors that still retain RNA) and CD45+, leukocytes from individuals with and without chronic pain, and longitudinal collections obtained at steady state, in VOC, and VOC resolution, and submitted these samples to TOPMed for RNASeq analysis. We propose to leverage this transcriptome data from a well phenotyped pediatric SCD cohort to address the unmet need of objective, quantifiable markers of acute and chronic pain, and evaluate in the context of the germline and somatic mutations found in the same subjects’ whole genome sequencing (WGS) data, also in TOPMed. Short term goals are to 1) identify genes and pathways altered in the chronic pain state, 2) identify transcriptome changes associated with pain events and their resolution, 3) generate a transcriptional risk score for the development of chronic pain, and 4) determine which variants associated with chronic pain development are likely to be causative through transcriptome wide association studies. Long term goals are to use these findings to 1) develop targeted therapies to prevent and treat VOC, 2) therapies to treat chronic pain in SCD, and 3) biomarkers to distinguish acute pain events from chronic pain. The ability to do so will allow providers to manage VOC appropriately and aggressively, without inadvertently confusing chronic pain with an acute pain episode. Our inability to distinguish between acute and chronic pain harms our patients, as the opioids that are the mainstay for VOC treatment often worsen chronic pain through opioid induced hyperalgesia. Our work will leverage TOPMed samples via our innovative transcriptomics analysis to identify risk factors, therapeutic targets, and biomarkers of chronic pain, in order to improve the care and quality of life of individuals living with SCD.

项目总结/摘要 镰状细胞病（SCD）患者在发病频率上表现出明显的个体间异质性 急性疼痛事件，或血管闭塞性危象（VOC）和慢性疼痛的发展。病灶 VOC的典型特征是白细胞粘附于内皮细胞，并伴随红细胞粘附于内皮细胞。 其脱氧和镰刀状，导致血管闭塞、局部缺血和疼痛。因此我们 从CD 71+细胞（仍保留RNA的红细胞前体）收集SCD患者RNA， CD 45+、慢性疼痛和非慢性疼痛个体的白细胞以及纵向采集 在稳定状态下获得VOC和VOC分辨率，并将这些样品提交给TOPMed 用于RNASeq分析。我们建议利用来自良好表型的转录组数据， 儿科SCD队列，以解决急性和慢性炎症客观、可量化标志物的未满足需求， 慢性疼痛，并在相同的生殖细胞和体细胞突变的背景下进行评估。 受试者的全基因组测序（WGS）数据，也在TOPMed中。短期目标：（1） 识别慢性疼痛状态下改变的基因和途径，2）识别转录组变化 与疼痛事件及其解决方案相关，3）生成用于疼痛事件的转录风险评分， 慢性疼痛的发展，以及4）确定哪些变体与慢性疼痛相关 通过全转录组关联研究，发育可能是致病的。长 长期目标是利用这些发现1）开发靶向治疗以预防和治疗VOC， 2)治疗SCD中的慢性疼痛的疗法，和3）区分急性疼痛事件与 慢性疼痛这样做的能力将使供应商能够适当地管理VOC， 积极地，没有无意中混淆慢性疼痛与急性疼痛发作。我们 无法区分急性和慢性疼痛会伤害我们的患者，因为阿片类药物 VOC治疗的主要手段经常通过阿片样物质诱导的痛觉过敏使慢性疼痛恶化。 我们的工作将通过我们创新的转录组学分析利用TOPM样本来识别 风险因素，治疗目标和慢性疼痛的生物标志物，以改善护理和 SCD患者的生活质量。