Functional and Integrative Omics of Recurrent Gout Flares

复发性痛风发作的功能和综合组学

• 批准号: 10271258
• 负责人: JEFFREY C EDBERG
• 金额: $ 39万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-25 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10271258
• 关键词: Acute; Address; Alabama; Allopurinol; Ancillary Study; Biological; Blood Cells; Blood specimen; CD14 gene; Caring; Cells; Clinical; Clinical Data; Clinical Trials; Collection; Crystallization; DNA Methylation; DNA methylation profiling; Data; Deposition; Enrollment; Epigenetic Process; Etiology; Exhibits; Flare; Funding; Gene Expression; Gene Expression Profile; Genes; Genetic Risk; Genetic Transcription; Genome; Gout; Grant; Hyperuricemia; Immune; Immunologics; In Vitro; Individual; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Investigation; Joints; Knowledge; Lead; Lipopolysaccharides; Literature; Mediating; Mendelian randomization; Methylation; Molecular; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Outcome; Parents; Participant; Pathogenesis; Patient Care; Patient Recruitments; Patients; Pattern; Precipitating Factors; Prevention therapy; Public Health; RNA; Recurrence; Registries; Regulation; Reporting; Role; Sampling; Serum; Techniques; Time; Training; Transcript; Translating; Translational Research; Ultrasonography; United States Department of Veterans Affairs; United States National Institutes of Health; Universities; Urate; X-Ray Computed Tomography; biobank; cell type; cohort; comorbidity; comparative efficacy; differential expression; effective therapy; experience; febuxostat; improved; improved outcome; insight; methylome; methylomics; monocyte; neutrophil; parent project; patient subsets; peripheral blood; primary outcome; recruit; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Monosodium urate crystals (MSU) activate inflammatory immune cells (e.g. monocytes/neutrophils), which potentiate acute gout attacks. Ultrasound and dual energy CT scans have shown the presence of MSU crystal deposits in joints of asymptomatic gout patients. These observations lead experts to agree that other unknown molecular factors are triggers for gout and recurrent flares. Our ancillary project's aims address two main questions: 1) Do neutrophils and/or monocytes, upon ex vivo activation by MSU crystals, exhibit gene expression and DNA methylation differences between gout patients with recurrent gout flares compared to those that do not? 2) Among gout patients from a clinical trial setting, where treat-to-target urate lowering therapy (ULT) is administered, are there gene expression and DNA methylation differences from the peripheral blood between individuals with or without recurrent flares? In aim 1 in a mechanistic/functional approach we will isolate neutrophils and CD14+ monocytes using fresh samples of peripheral blood from gout patients newly recruited into UAB's Gout Registry, the time sensitive parent project for this R01. The UAB Gout Registry is administered by UAB's NIAMS funded Center of Research Translation (CORT) “INvestigationS In Gout, Hyperuricemia, and comorbidiTies (INSIGHT)” (NIH P50 060772), which is the parent project for our ancillary study. The cells will be activated with MSU and we will use RNAseq to compare gene expression between groups (recurrent flares vs no flares). We will determine whether DNA methylation changes may be associated with observed transcription differences. In aim 2 we will utilize clinical data and biological samples from the clinical trial, VA-CSP594, the “Stop Gout” trial. The trial is a non-inferiority comparison between the ULT agents, febuxostat and allopurinol, of the primary outcome, the proportion of participants who flare at least once. The Stop Gout trial organizers agreed to augment their biospecimen collection to allow the collection of RNA for our ancillary study. We will analyze ~300 samples of RNA from the trial's participants. We will compare baseline gene expression and DNA methylation associations with recurrent flares. We will utilize Mendelian randomization to assess the causality of differentially methylated CpGs and expressed transcripts with recurrent gout flares. The results from aims 1 and 2 will expand our knowledge of the transcriptomic and methylomic changes that precipitate gout flares, which will translate to improved gout patient care and treatment.

项目总结 尿酸单钠晶体(MSU)激活炎症免疫细胞(例如单核细胞/中性粒细胞)，这是 加强急性痛风发作。超声波和双能CT扫描显示MSU晶体的存在 无症状痛风患者关节内沉积。这些观察结果使专家们一致认为，其他未知因素 分子因素是痛风和反复发炎的诱因。我们的辅助项目的目标主要有两个 问题：1)中性粒细胞和/或单核细胞在被MSU晶体体外激活后是否表现出基因 痛风反复发作患者的基因表达和DNA甲基化的差异 那些没有？2)来自临床试验环境的痛风患者，其中治疗与目标尿酸降低 接受治疗(ULT)后，患者外周血中的基因表达和DNA甲基化是否存在差异 有没有反复出现耀斑的个体之间的血液？在目标1中，在机械/功能方法中，我们 将使用痛风患者的新鲜外周血样本分离中性粒细胞和CD14+单核细胞 招募到UAB的痛风登记处，这是这个R01的时间敏感的父项目。UAB Gout注册表是 由UAB的NIAMS资助的研究翻译中心(CORT)管理， 高尿酸血症和合并症(洞察力)“(美国国立卫生研究院P50 060772)，这是我们附属项目的母项目 学习。细胞将被MSU激活，我们将使用RNAseq来比较 两组(反复出现照明弹与没有照明弹)。我们将确定DNA甲基化变化是否可能与 与观察到的转录差异。在目标2中，我们将利用来自 临床试验，VA-CSP594，“止痛风”试验。这场审判是一次非自卑的比较， 药物，非布索斯特和别嘌醇，的主要结果，参与者至少有闪光的比例 一次。Stop Gout试验的组织者同意增加他们的生物显微镜收集，以允许收集 用于我们辅助研究的RNA。我们将分析约300份来自试验参与者的RNA样本。我们会 比较基线基因表达和DNA甲基化与复发红斑的相关性。我们将利用 孟德尔随机法评估差异甲基化的CPGS和表达的转录本的因果关系 反复出现痛风发作。AIMS 1和AIMS 2的结果将扩大我们对转录和 引发痛风发作的甲基化改变，这将转化为改善痛风患者的护理和 治疗。