Cystic fibrosis (CF) is one of the most common and deadly genetic disorders, affecting ~1/3,000 live births in the United States. The responsible genetic mutations are linked to the gene that encodes CF Transmembrane-conductance Regulator (CFTR), a cAMP-activated chloride channel. Although this disease affects almost all organs and systems, its lung complications claim the most morbidity and mortality. The prominent lung pathology is marked by chronic bacterial infection, persistent neutrophilic inflammation, and purulent small airway obstruction, of which persistent lung inflammation is responsible for lung structure damage and function loss. Even though the CF molecular defect was discovered three decades ago, the link between the CFTR chloride channel defect and the destructive lung inflammation has not been defined. Such a knowledge gap impedes any informed development of effective therapies for CF. The current proposal is to address this outstanding problem in the field. Our overarching hypothesis is that CFTR loss-of-function in marrow-derived innate immune cells compromises their ability to molecularly modify and functionally deactivate inflammatory agonists, leading to excessive stimulation and neutrophilic inflammation in CF lungs. To test this hypothesis, we propose three specific aims:
Aim 1 : Determine that lineage-specific CFTR loss-of-function in neutrophils and monocytes/macrophages leads to persistent neutrophilic inflammation in the lung differentially;
Aim 2 : Determine that CF lung neutrophilic inflammation is due to neutrophil excessive recruitment, reduced apoptosis, and/or inefficient efferocytosis;
Aim 3 : Define that CF neutrophils and macrophages are compromised in chemical modification and functional deactivation of neutrophil chemotactic factors. Completion of this research will provide novel insights into CF lung disease pathogenesis. The new knowledge obtained will guide the rational design of interventions for effective treatment of this devastating disease.

Public Health Relevance

Excessive neutrophil-dominant inflammation is a major clinical problem that destroys the lung structure and function in the patients with cystic fibrosis (CF), which claims over 90% of deaths of all CF patients. This application has laid out a comprehensive plan to discover a major defect of CF that lies in the lung-recruited innate immune cells, and is responsible for the lethal lung complication. The outcome of this research will reveal new therapeutic target for pharmaceutical or genetic interventions of the disease for cure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL150370-01A1
Application #
10052074
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Lachowicz-Scroggins, Marrah Elizabeth
Project Start
2020-09-01
Project End
2024-07-31
Budget Start
2020-09-01
Budget End
2021-07-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Louisiana State Univ Hsc New Orleans
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112