COVID-19: Multi-Omics Approach to Identify Molecular Mechanisms Responsible for Risk and Resilience to Adverse Outcomes

COVID-19：多组学方法来识别导致风险和不良结果恢复能力的分子机制

• 批准号: 10154323
• 负责人: CHARLES D SEARLES
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10154323
• 关键词: 2019-nCoV; Address; African American; Age; Angiotensin II; Arrhythmia; Attenuated; Biochemical Pathway; Biological; Biological Markers; Blood; Blood Banks; Blood specimen; Brain natriuretic peptide; C-reactive protein; COVID-19; COVID-19 mortality; COVID-19 pandemic; COVID-19 patient; COVID-19 test; COVID-19 testing; Cardiovascular Diseases; Cardiovascular system; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; China; Clinical; Clinical Data; Congestive Heart Failure; Coronary Arteriosclerosis; Data; Databases; Development; Diabetes Mellitus; Disease; Disease Outcome; Disease Progression; Electronic Health Record; Enrollment; Epidemic; Epigenetic Process; Ethnic Origin; Europe; Fibrin fragment D; Fibrin split products; Health; High Prevalence; Hypertension; Immune; Immune response; Immunologic Markers; Infarction; Infection; Inflammation; Infrastructure; Interleukin-6; International; Intervention; Laboratories; Lead; Left; Logistic Regressions; Measurement; Measures; Mechanical ventilation; Medical center; Metabolic; Metabolic Pathway; Methods; MicroRNAs; Modeling; Molecular; Molecular Profiling; Myocardial; Myocarditis; Obesity; Outcome; Oxidative Stress; Participant; Pathologic; Pathway interactions; Patients; Pilot Projects; Plasma; Play; Positioning Attribute; Predisposition; Proteomics; Protocols documentation; Race; Renin; Renin-Angiotensin-Aldosterone System; Research; Residual state; Risk; Risk Factors; Role; SARS-CoV-2 infection; Sampling; Severity of illness; Stretching; Structure of respiratory epithelium; Testing; Therapeutic; Therapeutic Intervention; Troponin I; University Hospitals; Urokinase Plasminogen Activator Receptor; Veterans; Virus Diseases; Work; acute infection; adverse outcome; aminothiol; angiotensin I (1-7); biobank; cardiometabolic risk; cardiometabolism; cardiovascular health; cardiovascular risk factor; cell injury; clinical predictors; clinically relevant; cohort; differential expression; experience; extracellular; feature selection; heart circulation; hemodynamics; high risk; immune activation; indicated prevention; inflammatory marker; lung injury; member; men; metabolome; metabolomics; military veteran; molecular marker; mortality risk; multiple omics; myocardial injury; new therapeutic target; next generation sequencing; novel; novel marker; pandemic disease; patient registry; personalized intervention; precision medicine; predictive marker; predictive modeling; primary endpoint; prognostic; programs; prospective; repository; resilience; screening; secondary endpoint; severe COVID-19; sex; specific biomarkers; systemic inflammatory response; targeted treatment; therapeutic target; thrombogenesis

Objective: Emerging data from the COVID-19 pandemic indicate that men and African Americans have higher mortality, and cardiometabolic risk factors, including obesity, diabetes, and hypertension, cluster in patients who develop adverse outcomes to SARS-CoV-2 infection. The Veteran population is particularly vulnerable to COVID-19 because of the very high prevalence of cardiometabolic risk factors. However, not all Veterans with COVID-19 experience severe disease, and there is an urgent need to identify novel molecular pathways underlying risk and resilience to COVID-19. Previous work and preliminary studies from our team have demonstrated that targeted proteomics, metabolomics, and miRNA-omics can identify novel biomarkers and molecular pathways associated with cardiovascular health and disease. In this project, we will use a multi-omics to elucidate novel biomarkers and pathways associated with risk and resilience to severe COVID-19. Research Plan: In Aim 1, we will compare expression of pathway-specific biomarkers in hospitalized patients with severe COVID-19 with expression of these biomarkers in patients who do not develop severe COVID-19. Pathway-specific biomarkers reflecting activation of the renin-angiotensin-aldosterone system, systemic inflammation, oxidative stress, immune activation, thrombogenesis, and myocardial injury and stretch will be assessed. The primary endpoints for severe disease will be pathologic elevation of IL-6 levels or troponin I levels. Secondary endpoints will be requirement for mechanical ventilation, congestive heart failure, change in SOFA score, and death. In Aim 2, we will assess the extracellular miRNA and metabolomic profiles of the same two groups of hospitalized COVID-19 patients and determine miRNAs and metabolites differentially expressed between the two groups. Subsequently, we will examine connectivity between miRNA-metabolome networks and clinical endpoints in COVID-19 patients by performing an integrative analysis of differentially expressed miRNAs and metabolites, which will identify metabolic pathways associated with severe infection. Methods: The proposed studies will analyze de-identified blood samples and clinical data from COVID-19 patients hospitalized at the Atlanta VAMC and Emory University Hospital. The samples will be obtained from a bio repository that is currently banking residual plasma and serum from routine laboratory testing of COVID-19 patients. In Aim 1, we will measure levels of aminothiol (oxidative stress), suPAR (thrombogenesis/immune dysregulation), hsCRP (inflammation), hsTnI (myocardial injury), BNP (myocardial stretch), D-dimers (thrombogenesis), angiotensin II, angiotensin-(1-7) and plasma renin activity. Logistic regression modeling will be performed to identify biomarkers predictive of clinical endpoints. In Aim 2, we will use next generation sequencing, RT-qPCR, and high-throughput metabolomics profiling to assess expression of extracellular miRNAs and metabolites. A metabolome wide association study (MWAS) and ensemble feature selection (EFS) will be used to identify robust biomarkers and develop predictive models for severe COVID-19. Data from EFS analysis will input to the program xMWAS, which will determine connectivity between miRNA-metabolome networks and clinical outcomes. Clinical Relevance: Veterans with cardiovascular conditions are at higher risk for SARS-CoV-2 infection and severe disease progression. Our team has the infrastructure and methods in place to conduct in-depth, multi- omics studies to address predictors of adverse outcomes in Veterans with COVID-19 and identify epigenetic and cardiometabolic pathways that determine susceptibility to adverse outcomes. Furthermore, because 50% of the Veteran population at the Atlanta VA Medical Center Veteran is African American, we are in a unique position to address the role of race in susceptibility to severe COVID-19. Discovery of novel biomarkers and pathways associated with severe COVID-19 has broad implications for screening, therapeutics, and implementation of earlier personalized interventional strategies for attenuating adverse outcomes.

目的：来自COVID-19大流行的新兴数据表明，男人和非裔美国人的数据更高 死亡率和心脏代谢危险因素，包括肥胖，糖尿病和高血压，群集在患者中 对SARS-COV-2感染产生不利结果。退伍军人人口特别容易受到 COVID-19，由于心脏代谢危险因素的流行率很高。但是，并不是所有的退伍军人 COVID-19经历严重疾病，迫切需要识别新的分子途径 对COVID-19的潜在风险和韧性。我们团队的先前工作和初步研究 证明靶向蛋白质组学，代谢组学和miRNA-omics可以识别新型的生物标志物和 与心血管健康和疾病相关的分子途径。在这个项目中，我们将使用多摩斯 阐明了与严重的Covid-19的风险和韧性相关的新型生物标志物和途径。 研究计划：在AIM 1中，我们将比较住院患者的途径特异性生物标志物的表达 在不出现严重的COVID-19的患者中，与这些生物标志物的表达相严重，并表达了这些生物标志物。 反映肾素 - 血管紧张素 - 醛固酮系统激活的途径特异性生物标志物，全身性 炎症，氧化应激，免疫激活，血栓形成以及心肌损伤和拉伸将是 评估。严重疾病的主要终点是IL-6水平或肌钙蛋白I水平的病理升高。 次要终点是机械通气，充血性心力衰竭，沙发的变化所必需的 得分和死亡。在AIM 2中，我们将评估相同两个的细胞外miRNA和代谢组谱 一组住院的Covid-19患者，并确定miRNA和代谢物差异表达 在两组之间。随后，我们将检查miRNA-Metabolome网络之间的连通性 通过对差异表达的综合分析，COVID-19患者的临床终点 miRNA和代谢物，将鉴定与严重感染相关的代谢途径。 方法：拟议的研究将分析COVID-19的去识别的血液样本和临床数据 患者在亚特兰大VAMC和埃默里大学医院住院。样品将从 生物存储库目前是COVID-19的常规实验室测试中的残留等离子体和血清 患者。在AIM 1中，我们将测量氨基硫醇的水平（氧化应激），Supar（血栓形成/免疫 失调），HSCRP（炎症），HSTNI（心肌损伤），BNP（心肌拉伸），D二聚体 （血栓形成），血管紧张素II，血管紧张素 - （1-7）和血浆肾素活性。逻辑回归建模将 进行以识别预测临床终点的生物标志物。在AIM 2中，我们将使用下一代 测序，RT-QPCR和高通量代谢组学分析，以评估细胞外的表达 miRNA和代谢产物。代谢组广泛的协会研究（MWAS）和集合特征选择（EFS） 将用于识别强大的生物标志物并为严重的Covid-19开发预测模型。来自EFS的数据 分析将输入XMWA的程序，该程序将确定miRNA-Metabolome之间的连通性 网络和临床结果。 临床相关性：患有心血管疾病的退伍军人对SARS-COV-2感染和 严重的疾病进展。我们的团队拥有基础架构和方法，可以进行深入，多重的 OMICS研究旨在解决COVID-19的退伍军人的不良后果的预测指标，并确定表观遗传和 确定对不良结果的敏感性的心脏代谢途径。此外，因为50％ 亚特兰大弗吉尼亚州医学中心退伍军人的资深人口是非裔美国人，我们处于独特的位置 探讨种族在对严重covid-19的敏感性中的作用。发现新颖的生物标志物和路径 与严重的Covid-19有关的筛查，治疗学和实施具有广泛的影响 较早的个性化介入策略，以减轻不良后果。