Clinical Phenotyping and Human Core

临床表型和人类核心

基本信息

批准号：
10696956
负责人：
RICHARD G WUNDERINK
金额：
$ 23.42万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10696956
关键词：
2019-nCoV Acute Renal Failure with Renal Papillary Necrosis Acute Respiratory Distress Syndrome Address Affect Alveolar Animal Model Animals Antibiotics Biological Biological Markers Bronchoalveolar Lavage Bronchoalveolar Lavage Fluid COVID-19 COVID-19 pandemic COVID-19 pneumonia Catabolism Cause of Death Cell model Cells Cessation of life Clinical Communicable Diseases Country Critical Care Data Death Certificates Death Rate Discrimination Encephalopathies Failure Flow Cytometry Functional disorder Funding Opportunities Goals Grant Human Immune Immune system Infection Inflammation Inflammatory Influenza Influenza A virus Infrastructure Injury Instruction International Intubation Knowledge Liquid substance Liver Dysfunction Lower Respiratory Tract Infection Lung Mechanical ventilation Modeling Modernization Mus Muscle National Institute of Allergy and Infectious Disease Nosocomial pneumonia Organ Organ failure Oseltamivir Outcome Pathway interactions Patients Pattern Phenotype Pneumonia Population Population Study Protein Analysis Protocols documentation Publishing Recovery Research Research Personnel Resolution Resources Respiratory Tract Infections Sampling Sepsis Sorting Streptococcus pneumoniae Systems Biology Therapeutic Intervention Time United States Universities Vasoconstrictor Agents Viral Viral Pneumonia Virus antimicrobial chemokine chronic infection clinical phenotype clinically relevant co-infection community acquired pneumonia epigenomics influenza pneumonia lung failure lung injury lung repair metabolomics microbiome alteration mortality mouse model pathogen pathogenic bacteria pathogenic virus pneumonia treatment programs remdesivir repaired respiratory virus response sepsis induced ARDS severe COVID-19 superinfection transcriptomics

项目摘要

PROJECT SUMMARY CORE B Lower respiratory tract infections cause nearly 80% of deaths from infectious diseases in the US, and respiratory viruses, such as influenza and SARS-CoV-2, are increasingly recognized as common causes of severe community-acquired pneumonia (CAP). As mortality from severe CAP persists despite appropriate antimicrobial treatment and clearance of the causative pathogen, Program Project Investigators hypothesize that mortality and persistent organ failure in severe viral CAP represent persistent inflammatory injury and a failure of lung repair mechanisms. Persistent inflammation and unrepaired organ damage drive poor long-term outcomes following severe CAP, and biomarkers suggest that patients with poor outcomes from severe CAP have a persistent pro-inflammatory state despite clearance of the presumed pathogen. Core B will allow Project Investigators to validate findings from causal murine and cell models of influenza pneumonia in patients with severe CAP induced by viral pathogens. The major goal of Core B is to provide serial bronchoalveolar lavage (BAL) samples obtained from well-phenotyped patients with severe influenza and SARS-CoV-2 pneumonia to the Project Investigators, as defined in the following Specific Aims: 1) Provide BAL fluid from intubated patients with influenza and SARS-CoV-2 pneumonia for a) flow cytometry-sorted BAL alveolar immune cell subsets for transcriptomic and epigenomic analysis and b) cell-free supernatant fluid for metabolomic and biomarker/protein analyses. 2) Define the microbiologic milieu at each BAL sampling time point regarding a) the presence of viral pathogens (viral PCR), b) the presence of bacterial co-infection (culture and PCR), and c) microbiome alterations. 3) Apply robust clinical phenotypes and relevant clinical endpoints. Core B will leverage the existing infrastructure of the Successful Clinical Response In Pneumonia Therapy (SCRIPT) Systems Biology Center at Northwestern University and its rigorous published protocols for flow cytometry sorting of alveolar immune cell populations, microbiologic analysis, and clinical phenotyping. Ultimately, the goal of this PPG is to define immune system pathways and mechanisms of failed resolution and repair following influenza and SARS-CoV-2 pneumonia that are amenable to therapeutic interventions. Core B is integral to supporting this goal by demonstrating strong clinical correlations to findings from the proposed murine models.

项目概要核心 B 在美国，下呼吸道感染导致近 80% 的传染病死亡，而呼吸道感染流感和 SARS-CoV-2 等病毒越来越被认为是导致重症的常见原因社区获得性肺炎（CAP）。尽管采取了适当的措施，严重 CAP 的死亡率仍然持续存在项目研究人员假设抗菌治疗和清除致病病原体严重病毒性 CAP 中的死亡率和持续性器官衰竭代表持续性炎症损伤和肺修复机制失效。持续的炎症和未修复的器官损伤导致长期贫困严重 CAP 后的结局和生物标志物表明，严重 CAP 结局不佳的患者尽管假定的病原体已被清除，但仍具有持续的促炎状态。核心 B 将允许项目研究人员验证流感肺炎患者的致病小鼠和细胞模型的发现由病毒病原体引起的严重CAP。 Core B 的主要目标是提供串行支气管肺泡从患有严重流感和 SARS-CoV-2 的表型良好的患者获得的灌洗 (BAL) 样本向项目研究人员提供肺炎，具体目标如下： 1) 提供 BAL 液体来自流感和 SARS-CoV-2 肺炎插管患者的 a) 流式细胞术分选的 BAL 肺泡用于转录组和表观基因组分析的免疫细胞亚群和 b) 用于分析的无细胞上清液代谢组学和生物标志物/蛋白质分析。 2) 定义每个 BAL 采样时间的微生物环境关于以下几点：a) 病毒病原体的存在（病毒 PCR），b) 细菌共感染的存在（培养和 PCR)，以及 c) 微生物组改变。 3) 应用稳健的临床表型和相关的临床终点。核心 B 将利用肺炎治疗成功临床反应的现有基础设施（SCRIPT）西北大学系统生物学中心及其严格发布的流式协议肺泡免疫细胞群的细胞计数分选、微生物分析和临床表型分析。最终，该 PPG 的目标是定义免疫系统途径和失败的解决机制以及流感和 SARS-CoV-2 肺炎后的修复可以接受治疗干预。核心B 通过证明与拟议研究结果的强烈临床相关性，对于支持这一目标是不可或缺的小鼠模型。