P01HL154998

Mechanisms of Recovery from Viral Pneumonia - Project Summary

Overall recovery from viral pneumonia is a clinically important yet understudied process. Severe influenza A virus and severe acute respiratory syndrome coronavirus 2 cause severe viral pneumonia, which damages the lower respiratory tract and induces acute respiratory distress syndrome (ARDS). Most ARDS deaths occur days-to-weeks after ARDS onset—a time when patients are recovering from the inciting insult. However, studies in murine models typically focus on the early development of acute lung injury and death from overwhelming infection.

Other than avoidance of additional lung injury, via low tidal volume ventilation and a handful of other supportive therapies, there are no specific therapies for patients with viral pneumonia-induced ARDS. A central hypothesis of this PPG (Program Project Grant) is that the persistence of respiratory failure and the development of multiple organ dysfunction in patients with ARDS is a consequence of the failure of normal mechanisms of inflammation resolution and lung tissue repair. This hypothesis is clinically supported by a recent analysis of patients enrolled in the ARDSNET, where a "hyperinflammatory" endotype of ARDS patients was associated with worse clinical outcomes, including death.

We propose to investigate the process of recovery from viral pneumonia with a focus on mechanisms that promote resolution of lung inflammation and healthy repair of lung damage. The PPG investigators will test this central hypothesis through a highly integrated and innovative set of experiments by focusing on four specific aims:

Specific Aim 1: To determine whether vimentin regulates persistent inflammation during recovery from severe influenza A virus-induced pneumonia by promoting a pro-inflammatory phenotype in monocyte-derived alveolar macrophages and by limiting the pro-repair capacity of regulatory T cells.

Specific Aim 2: To determine whether mitochondrial electron transport chain complex I or III, and lactate production, drives persistent NLRP3 inflammasome-dependent inflammation during recovery from severe influenza A virus-induced pneumonia.

Specific Aim 3: To determine whether persistent activation of LUBAC-mediated NF-KB signaling in the lung epithelium drives macrophage activation and inhibits lung repair following viral pneumonia.

Specific Aim 4: To determine whether DNA methyltransferase activity and UHRF1 induce DNA hypermethylation in Treg cells during aging to impair Treg cell reparative function following severe viral pneumonia in older hosts.

Northwestern University

THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Chicago, Illinois 606113015 United States

Single Zip Code

NHLBI Program Project Applications (P01 - Clinical Trials Optional) (PAR-18-405)

Amendment Since initial award the total obligations have increased 364% from $2,848,690 to $13,214,298.