Peripheral Blood Exosome Lipids as Biomarkers of Disease Activity in Crohn’s Disease

外周血外泌体脂质作为克罗恩病疾病活动的生物标志物

• 批准号: 9767782
• 负责人: Terrence A. Barrett
• 金额: $ 19.27万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767782
• 关键词: Address; Biological Markers; C-reactive protein; Cells; Charge; Clinical; Clinical assessments; Clostridium difficile; Consensus; Control Groups; Crohn' s disease; Data; Data Set; Dendritic Cells; Development; Diagnostic; Disease; Disease remission; Endoscopy; Epithelial Cells; Goals; Image; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestines; Kentucky; Knowledge; Leukocyte L1 Antigen Complex; Leukocytes; Link; Lipids; Longitudinal Studies; Mass Spectrum Analysis; Medical; Mesenchymal; Newly Diagnosed; Pathology; Patient Monitoring; Patients; Pattern; Plasma; Principal Component Analysis; Process; Public Health; Refractory; Research; Resolution; Sampling; Sensitivity and Specificity; Speed; Structure; Testing; Tissues; Universities; Work; base; clinical research site; design; disorder control; exosome; follow-up; improved; indexing; individual patient; macrophage; mass spectrometer; neutrophil; novel; novel therapeutics; peripheral blood; response; sample collection; specific biomarkers; tool

Abstract Management of inflammatory bowel disease (IBD) patients requires knowledge of disease status to inform treatment decisions. Commonly used biomarkers such as clinical disease activity indices, C reactive protein (CRP) and fecal calprotectin achieve suboptimal sensitivity and specificity for intestinal inflammation1. Data provided indicate that peripheral blood exosome (PBE) lipid composition distinguishes active IBD from normal patients (Fig. 1). We contend that PBE lipid compositions will provide clinicians with a highly sensitive and specific biomarker to assess disease activity without invasive testing. The need to identify subtle disease derives from the consensus conclusion that “deep remission” should be the endpoint of therapy. Thus, monitoring of patients with intent to suppress subclinical inflammation has emerged as a treatment goal3. Exosomes are lipid-encased, subcellular (60-80 nm) structures released into the peripheral blood at from intestinal epithelial cells (IEC), activated leukocytes (e.g. neutrophils, macrophages, dendritic cells, etc.) and mesenchymal cells during inflammation3. We used an ultrahigh resolution Orbitrap mass spectrometer to analyze lipid compositions of PBEs from patients (>25/group). Principal component analysis (PCA) of PBE lipid intensities showed a wide separation of datapoints between active IBD and normal controls and a heatmap analysis of differential abundance revealed high within-group correlations and low between-group correlations suggesting that distinct lipids can be resolved that correlate with disease activity. In this two year project, we propose to collect plasma from 1) moderate-severe, 2) mildly-active and 3) quiescent Crohn’s disease (CD) patients as well as inflammatory (C. difficile-infected) and 4) normal controls. Using CD allows us to test whether PBE composition detects levels of mild (in many cases, subclinical) disease activity as this identifies patients not in deep remission, a goal of medical therapy. In Aim 1, PBE lipid-based classifiers will be developed to discriminate mildly-active from severely-active CD and controls. In Aim 2, PBE lipids will be examined longitudinally within individual patients before and after therapy to identify lipids correlate with clinical response. Such information will also be passed to Aim 1 to develop more robust classifiers. Testing patterns of PBE lipids in responsive and refractory patients is intended to improve the robustness of the classifiers. Studies in Aim 1 and 2 are greatly enhanced by the inclusion of a second clinical site (Baylor University) to provide samples to validate (or not) data from University of Kentucky. The long-term goal will be to justify studies to identify a “exosomal lipid signature” panel that provide a novel set of biomarkers for discriminating levels of CD disease activity and informing treatment decisions. We post that the creation of a CD exosome lipid biomarker test will obviate the need for follow-up endoscopy in the majority of patients.

抽象的 炎症性肠病（IBD）患者的管理需要了解疾病状况以告知 治疗决定。常用的生物标志物，例如临床疾病活动指数，C反应性蛋白 （CRP）和粪便钙骨蛋白具有肠道注射的次优敏感性和特异性1。数据 提供的迹象表明外周血外泌体（PBE）脂质成分将活动的IBD与 正常患者（图1）。我们认为PBE脂质成分将为临床医生提供高度敏感的 和特定的生物标志物评估疾病活动而无需侵入性测试。需要识别微妙的疾病 得出的结论是，“深度缓解”应该是治疗的终点。那， 监测意图抑制亚临床炎症的患者已成为治疗 目标3。外泌体是基于脂质的，基于脂质的亚细胞（60-80 nm）结构，释放到外周血 来自肠上皮细胞（IEC），活化的白细胞（例如中性粒细胞，巨噬细胞，树突状细胞等） 炎症期间的间充质细胞3。我们使用了超高的分辨率轨道质谱仪 分析患者PBE的脂质组成（> 25/组）。 PBE脂质的主成分分析（PCA） 强度显示活动的IBD和正常对照与热图之间的数据点广泛分离 分析差异丰度揭示了较高的组内相关性和较低的组间相关性 表明可以解决与疾病活性相关的不同脂质。在这个为期两年的项目中，我们 提议从1）中等重度收集血浆，2）轻度活跃和3）静态的克罗恩病（CD） 患者以及炎症性（艰难梭菌感染）和4）正常对照。使用CD使我们可以测试 PBE组成是否检测到轻度（在许多情况下，亚临床）疾病活动的水平，因为这 患者没有严重缓解，这是医疗治疗的目标。在AIM 1中，基于PBE脂质的分类器将是 开发是为了区分严重活跃的CD和对照。在AIM 2中，PBE脂质将是 在治疗前后，在个别患者中纵向检查，以鉴定脂质与临床相关 回复。此类信息也将传递给AIM 1，以开发更强大的分类器。测试模式 反应性和难治性患者中的PBE脂质旨在改善分类器的鲁棒性。 通过将第二个临床部位（贝勒大学）纳入AIM 1和2的研究大大增强了 提供样品来验证肯塔基大学的数据（或没有）数据。长期目标是证明 识别“外泌体脂质签名”面板的研究，该面板提供了一组新型的生物标志物来区分 CD疾病活动水平并为治疗决定提供了信息。我们发布CD外泌体的创建 脂质生物标志物测试将消除大多数患者的后续内窥镜检查的必要性。

项目成果

Editorial: opioids in inflammatory bowel disease-primum non nocere. Authors' reply.

社论：阿片类药物在炎症性肠病中的应用-primum non nocere。

• DOI: 10.1111/apt.16292
• 发表时间: 2021
• 期刊: Alimentary pharmacology & therapeutics
• 影响因子: 7.6
• 作者: Rhudy,Christian;Perry,CourtneyL;Barrett,TerrenceA
• 通讯作者: Barrett,TerrenceA