Omics-Based Predictive Modeling of Age-Dependent Outcome to Influenza Infection

基于组学的流感感染年龄依赖性结果预测模型

• 批准号: 8896419
• 负责人: Elodie Ghedin
• 金额: $ 262.87万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896419
• 关键词: Adult; Affect; Age; Animal Model; Bedside Testings; Behavior; Binding; Biological; Biological Markers; Cessation of life; Clinical; Complex; Computer Simulation; Data; Development; Diabetes Mellitus; Disease; Disease Outcome; Ferrets; Goals; Hospitalization; Human; Immune response; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Instruction; Interleukin-17; Interleukin-6; Lower respiratory tract structure; Measurement; Morbidity - disease rate; Neonatal; Outcome; Patients; Physiological; Prognostic Marker; Public Health; RNA; Respiratory Tract Diseases; Risk; Risk Factors; Sampling; Severities; System; TNF gene; Tissues; Transcript; Translating; Viral; Virus Diseases; Whole Organism; age related; aged; base; data modeling; mathematical model; mortality; outcome forecast; pathogen; preclinical study; predictive modeling; protein metabolite; respiratory; response; trait; transcriptomics; virus host interaction

Influenza is a major public health concern around the world and determining the prognosis of an infected patient who was otherwise healthy is often a major challenge. In 2009, infections with the H1N1 strain resulted in 274,000 hospitalizations and 12,470 deaths. Risk factors for morbidity and mortality include age, co-morbid illness, such as diabetes meNitus, and lower respiratory tract disease. Viral infection is initiated in the upper ainway and, in severe cases, followed by progression to lower tract disease. In both human studies and pre-clinical animal models, several biomarkers have been associated with more severe disease, including TNF-a, IL-6, and IL-17. Host response to influenza infection is a complex trait that involves entire host-pathogen interaction networks of RNA transcripts, proteins and metabolites impacting cellular, tissue and whole organism behaviors that ultimately define both the risk and severity of infection. The complex array of these interacting factors affect entire network states that in turn increase or decrease the risk of infection or the severity of response to infection. The focus of our project is to integrate multi-scale data collected over the course of influenza infections-including system-wide transcriptomics and meta- transcriptomics, immunological response and physiological markers, along with viral diversity-in order to perform network analyses and develop computational models that predict severe disease outcome. Our goal is to leverage the power of high-dimensional, large-scale Omics data and mathematical modeling to identify risk-stratifying prognostic biomarkers that could be used in the development of point-of-care testing applicable to clinical respiratory samples to identify patients at risk for severe influenza disease. To achieve this goal, we will build predictive models from molecular interaction networks, translated to specific severity outcomes. We propose to use an age-dependent animal model (neonatal, adult and aged ferrets) and clinical human samples to collect biological measurements at multiple scales of host-virus interaction. RELEVANCE (See instructions):

流感是世界范围内的一个主要公共卫生问题，并决定了感染者的预后。 通常是一个重大的挑战。2009年，H1N1病毒感染 导致274 000人住院治疗，12 470人死亡。发病率和死亡率的风险因素包括年龄， 合并症，如糖尿病和下呼吸道疾病。病毒感染开始于 上尿路疾病，严重者发展为下尿路疾病。在这两项人类研究中 和临床前动物模型，几种生物标志物与更严重的疾病相关， 包括TNF-α、IL-6和IL-17。宿主对流感感染的反应是一个复杂的特征， 影响细胞、组织和免疫系统的RNA转录物、蛋白质和代谢物的宿主-病原体相互作用网络 以及整个生物体的行为，最终决定了感染的风险和严重程度。复杂 这些相互作用的因素会影响整个网络状态，进而增加或减少 感染或对感染反应的严重程度。我们项目的重点是整合多尺度数据 在流感感染过程中收集的数据，包括全系统转录组学和Meta分析， 转录组学、免疫反应和生理标记，沿着病毒多样性， 进行网络分析并开发预测严重疾病结果的计算模型。我们的目标 是利用高维、大规模组学数据和数学建模的力量来识别 可用于开发即时检测的风险分层预后生物标志物 适用于临床呼吸道样本，以识别存在严重流感疾病风险的患者。实现 为了实现这一目标，我们将从分子相互作用网络中建立预测模型， 结果。我们建议使用年龄依赖性动物模型（新生、成年和老年雪貂）， 临床人类样本，以收集宿主-病毒相互作用的多个尺度的生物学测量值。 相关性（参见说明）：