Genomic signatures for detection of upper respiratory viral infections

用于检测上呼吸道病毒感染的基因组特征

• 批准号: 8625188
• 负责人: Micah T. McClain
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8625188
• 关键词: Accident and Emergency department; Acute; Affect; Age; Bacteria; Biological Assay; Blood; Cessation of life; Chronic; Clinical; Comorbidity; Data; Detection; Disease; Elderly; Enrollment; Escherichia coli; Evolution; Exhibits; Factor Analysis; Funding; Gene Chips; Gene Expression; Genes; Genomics; Goals; Health; Health Status; Health system; Healthcare; Heart Diseases; Hospitalization; Human; Immune response; In Vitro; Individual; Infection; Influenza; Inpatients; Interview; Life; Long-Term Care; Lung diseases; Metabolic Diseases; Methods; Microarray Analysis; Mission; Modeling; Morbidity - disease rate; Mycoplasma; Nature; Older Population; Outpatients; Patients; Pattern; Performance; Peripheral Blood Mononuclear Cell; Persons; Physicians; Population; RNA; Rehabilitation Centers; Reporting; Research Personnel; Risk; Sampling; Serodiagnoses; Severity of illness; Streptococcus pneumoniae; Symptoms; Telephone; Testing; Time; Translational Research; United States; Upper Respiratory Infections; Variant; Veterans; Viral; Virus Diseases; Visit; Vulnerable Populations; Work; aging population; base; career development; cohort; community living; cost; cytokine; demographics; design; disease diagnosis; healthy volunteer; in vitro Model; influenzavirus; peripheral blood; productivity loss; public health relevance; respiratory; respiratory virus; response

DESCRIPTION (provided by applicant): The overall goal of this endeavor is to establish the Candidate as an independent scientific investigator through a carefully designed combination of career development activities and directed translational research. This project aims to define patterns of host gene expression which are capable of accurately classifying acute upper respiratory viral infection (URI) as well as predicting eventual disease severity from URIs in a population of US Veterans. This work represents a unique opportunity to utilize data collected as a part of DARPA- funded respiratory viral challenge studies in young, healthy individuals as a starting point to define the initiation nd evolution of the human response to infection in a more vulnerable population in keeping with the mission of the Veterans Affairs Health System. The objective of this application is to test and refine (where necessary) the applicability of genomic signatures to a more varied population of older Veterans whose health status is more likely to be complicated by age and multiple comorbidities which may alter the nature of the genomic response. This will be accomplished through the following Specific Aims: Aim 1. Derive host gene signatures that define upper respiratory viral infection in an aging population through use of an in vitro model. We will isolae and infect human Peripheral Blood Mononuclear Cells with influenza viruses in order to develop gene signatures which characterize infection. These PBMCs will be isolated from stable, non-acutely infected individuals selected from a population of US Veterans living in our Extended Care and Rehabilitation Center. The PBMCs will then be exposed in vitro to live respiratory viruses (Influenza, HRV, RSV) or bacteria (Streptococcus pneumoniae, Mycoplasma, or E. coli), and host RNA will be isolated at multiple timepoints and assayed by microarray for gene expression. Genomic signatures will then be analyzed through standard methods as well as by the modified sparse latent factor analysis we have previously developed for this purpose. Aim 2. Enroll and characterize a cohort of US Veterans with URI We will identify cases of Influenza-like illness in US Veterans through two major portals. The first will be to identify cases of ILI among individuals living in the DVAMC ECRC. The second will be to capture individuals presenting with ILI through the DVAMC Emergency Department. In both cases we will obtain peripheral blood RNA for microarray analysis at the time of presentation as well as standard samples for both microbiological and serological diagnosis. These individuals will be followed with daily symptom score reporting - inpatients in the ECRC through daily visits from study staff, and outpatients enrolled in the ED through daily phone interviews. Subjects enrolled in the ECRC will also have blood drawn daily throughout the course of disease for RNA isolation and microarray analysis as well as cytokine expression in order to characterize the evolution of the host response. Aim 3. Evaluate performance of URI gene signatures in an aging population. We will evaluate the performance of our genomic signatures identified a) in our previous studies with young, healthy volunteers and b) through our in vitro model of infection in Specific Aim 1 through application of these signatures to individuals who have presented with microbiologically proven Influenza infection as defined in Specific Aim 2. Aim 4. Evaluate new gene signature(s) specific to an aging population. We will derive new gene signatures based upon the data from Influenza infected individuals enrolled in Aim 2. Given potential differences in the populations, we will the cross-validate signatures derived from ECRC patients on signatures derived from ED-enrolled patients and vice versa. Furthermore, we will utilize variations in gene signatures at the time of presentation to build a genomic prediction model for eventual disease severity.

描述（由申请人提供）： 这一奋进的总体目标是通过精心设计的职业发展活动和定向转化研究的组合，将候选人确立为独立的科学研究者。该项目旨在定义宿主基因表达模式，这些模式能够准确分类急性上呼吸道病毒感染（URI），并预测美国退伍军人人群中URI的最终疾病严重程度。这项工作代表了一个独特的机会，利用作为DARPA资助的年轻健康个体呼吸道病毒挑战研究的一部分收集的数据作为起点，以确定更脆弱人群中人类对感染反应的起始和演变，以符合退伍军人事务卫生系统的使命。本申请的目的是测试和完善（必要时）基因组特征对更多样化的老年退伍军人人群的适用性，这些人群的健康状况更可能因年龄和多种合并症而复杂化，这可能会改变基因组应答的性质。这将通过以下具体目标来实现：目标1。通过使用体外模型推导出定义老年人群中上呼吸道病毒感染的宿主基因特征。 我们将用流感病毒分离和感染人外周血单核细胞，以开发表征感染的基因特征。这些PBMC将从生活在我们的扩展护理和康复中心的美国退伍军人人群中选择的稳定的非急性感染个体中分离。然后将PBMC在体外暴露于活的呼吸道病毒（流感病毒、HRV、RSV）或细菌（肺炎链球菌、支原体或大肠杆菌）。大肠杆菌），并在多个时间点分离宿主RNA，并通过微阵列测定基因表达。然后，将通过标准方法以及我们先前为此目的开发的修改后的稀疏潜在因子分析来分析基因组签名。目标2.招募并描述一组患有URI的美国退伍军人我们将通过两个主要门户网站识别美国退伍军人中的流感样疾病病例。第一项工作将是查明居住在DVAMC ECRC的个人中的ILI病例。第二个将是通过DVAMC急诊科捕获ILI患者。在这两种情况下，我们将获得外周血RNA用于微阵列分析，以及微生物学和血清学诊断的标准样品。将通过每日症状评分报告对这些个体进行随访-ECRC中的住院患者通过研究工作人员的每日访视进行随访，以及艾德中入组的门诊患者通过每日电话访谈进行随访。入组ECRC的受试者还将在整个疾病过程中每天抽血，用于RNA分离和微阵列分析以及细胞因子表达，以表征宿主应答的演变。目标3.评估URI基因签名在老龄化人群中的表现。我们将评估我们的基因组特征的性能，a）在我们之前对年轻健康志愿者的研究中，和B）通过我们在特定目标1中的体外感染模型，通过将这些特征应用于已经表现出微生物学证实的流感感染的个体，如特定目标2中所定义的。目标4。评估特定于老龄化人群的新基因特征。我们将根据Aim 2中入组的流感感染个体的数据得出新的基因特征。考虑到人群中的潜在差异，我们将交叉验证ECRC患者的签名与ED入组患者的签名，反之亦然。此外，我们将利用基因签名的变化，在演示时建立一个基因组预测模型，最终疾病的严重程度。