Clinical Phenotyping and Human Core

临床表型和人类核心

基本信息

批准号：
10269672
负责人：
RICHARD G WUNDERINK
金额：
$ 26.37万
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/10269672
关键词：
2019-nCoV Acute Renal Failure with Renal Papillary Necrosis Address Adult Respiratory Distress Syndrome Affect Alveolar Animal Model Animals Antibiotics Biological Markers Bronchoalveolar Lavage Bronchoalveolar Lavage Fluid COVID-19 COVID-19 pandemic COVID-19 pneumonia Catabolism Cause of Death Cell model Cells Centers for Disease Control and Prevention (U.S.)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 Knowledge Liquid substance Liver Dysfunction Lower Respiratory Tract Infection Lung Mechanical ventilation Microbiology 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 Failure Respiratory Tract Infections Sampling Sepsis Sorting - Cell Movement Streptococcus pneumoniae Systems Biology Therapeutic Intervention Time United States Universities Vasoconstrictor Agents Viral Viral Pneumonia Virus antimicrobial base chemokine chronic infection clinical phenotype clinically relevant co-infection community acquired pneumonia epigenomics influenza pneumonia lung injury lung repair metabolomics microbiome alteration mortality mouse model pathogen pathogenic bacteria pathogenic virus pneumonia treatment programs protein biomarkers remdesivir repaired respiratory virus response 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.

项目摘要核心B 下呼吸道感染导致美国感染性疾病的死亡人数近80％，呼吸道病毒，例如流感和SARS-COV-2，越来越多地被认为是严重的常见原因社区获得的肺炎（上限）。尽管适当计划研究人员假设抗菌治疗和因果病原体的清除率严重病毒帽中的死亡率和持续器官衰竭表示持续的炎症损伤和肺修复机制的失败。持续的炎症和未修复的器官损伤驱动不良的长期严重帽和生物标志物的结果表明，严重帽的结果差的患者尽管清除了假定的病原体，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来自因果鼠的发现和流感肺炎的细胞模型病毒病原体引起的严重帽。核B的主要目标是提供串行支气管肺泡从严重流感和SARS-COV-2的良好表现的患者获得的灌洗（BAL）样品肺炎向项目调查人员提供，如以下特定目的所定义：1）提供BAL流体来自流感和SARS-COV-2肺炎的插管患者a）流式细胞仪排序的BAL肺泡免疫细胞亚群，用于转录组和表观基因组分析以及b）无细胞上清液的液体代谢组和生物标志物/蛋白质分析。 2）在每个BAL采样时间定义微生物环境关于a）存在病毒病原体（病毒PCR）的点，b）存在细菌共感染（培养和PCR），以及C）微生物组改变。 3）应用可靠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（脚本）西北大学的系统生物学中心及其严格发布的流程协议肺泡免疫细胞群，微生物学分析和临床表型的细胞仪分选。最终，该PPG的目的是定义分辨率失败的免疫系统途径和机制经过治疗干预措施的流感和SARS-COV-2肺炎的维修。核心b 通过证明与拟议的发现的强烈临床相关性，是支持这一目标的不可或缺的一部分鼠模型。