Transcriptomics of Pain in Sickle Cell Disease

镰状细胞病疼痛的转录组学

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要镰状细胞病（SCD）患者在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危象 (VOC) 以及慢性疼痛的发展。 VOC 的典型特征是白细胞与内皮细胞的粘附，从而带来红细胞它会脱氧和镰刀状，导致血管闭塞、缺血和疼痛。从 CD71+ 细胞（仍保留 RNA 的红细胞前体）收集 SCD 患者 RNA，并 CD45+、患有和不患有慢性疼痛的个体的白细胞以及纵向收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 我们建议利用来自表型良好的转录组数据。儿科 SCD 队列，旨在解决急性和慢性疾病客观、可量化标志物的未满足需求慢性疼痛，并在同一疾病中发现的种系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，短期目标是 1) 识别慢性疼痛状态下改变的基因和通路，2) 识别转录组变化与疼痛事件及其解决相关，3) 生成转录风险评分慢性疼痛的发展，4) 确定哪些变异与慢性疼痛相关通过转录组范围的关联研究，发育可能是因果关系。长期目标是利用这些发现来 1) 开发有针对性的疗法来预防和治疗 VOC， 2) 治疗 SCD 慢性疼痛的疗法，以及 3) 区分急性疼痛事件和慢性疼痛的生物标志物这样做的能力将使提供者能够适当地管理 VOC。积极地，不会无意中将慢性疼痛与急性疼痛发作混淆。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 治疗的主要方法通常会通过阿片类药物引起的痛觉过敏而加重慢性疼痛。我们的工作将通过创新的转录组学分析利用 TOPMed 样本来识别慢性疼痛的危险因素、治疗目标和生物标志物，以改善护理和治疗 SCD 患者的生活质量。