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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.

项目总结