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.

项目摘要/摘要镰状细胞疾病（SCD）暴露于频率上的个体异质性的患者急性疼痛事件或血管熟悉的危机（VOC）和慢性疼痛的发展。 nidus VOC的通常是白细胞对内皮的粘附，带有红色细胞会脱氧和镰刀，导致血管酸酸，缺血和疼痛。因此，我们从CD71+细胞（仍然保留RNA的红细胞前体）和 CD45+，来自有或没有慢性疼痛的个体的白细胞，纵向收集在稳定状态，在VOC和VOC分辨率下获得，并将这些样品提交给用于RNASEQ分析。我们建议从表现良好的情况下利用此转录组数据小儿SCD队列，以满足对急性和可量化标记的未满足的需求慢性疼痛，并在同一种系和体细胞突变的背景下进行评估受试者的整个基因组测序（WGS）数据也是最高的。短期目标是1）识别慢性疼痛状态中改变的基因和途径，2）识别转录组变化与疼痛事件及其分辨率相关，3）产生转录风险评分慢性疼痛的发展，4）确定哪些与慢性疼痛相关的变体通过转录组广泛的关联研究，发展可能是一种致病性的。长的术语目标是将这些发现使用1）开发的有针对性疗法来预防和治疗VOC， 2）治疗SCD中慢性疼痛的疗法和3）生物标志物将急性疼痛事件与慢性疼痛。这样做的能力将使提供商可以适当地管理VOC和积极地，无意间将慢性疼痛与急性疼痛发作混淆。我们的无法区分急性和慢性疼痛会损害我们的患者，因为阿片类药物是 VOC治疗的主要手段通常通过阿片类药物诱导的痛觉过敏会加重慢性疼痛。我们的工作将通过我们的创新转录组学分析利用最佳样本来识别为了改善护理和 SCD生活的个人的生活质量。