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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：
10501596
负责人：
Vivien Andrea Sheehan
金额：
$ 39.62万
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/10501596
关键词：
ATAC-seq Acute Pain Address Adhesions Adult Affect American Biological Markers Blood Cells Caring Cells Childhood Chronic Collection 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 Hospitals Hyperalgesia Impairment Individual Inherited Injury Ischemia Lead 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 candidate marker 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 metabolomics methylomics multiple omics novel therapeutics opioid overuse pediatric patients precision medicine prevent sickling targeted biomarker 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.

项目总结/文摘