Targeting Lymphotoxin signalling to reverse tissue injury in COPD
Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease characterized by progressive and largely irreversible airflow limitation. It is a leading cause of chronic mortality and morbidity worldwide with no current therapies able to reverse disease progression. Long-term exposure to toxic gases and particles like cigarette smoke (CS), drives excess mucus production, small airway remodelling, chronic bronchitis and emphysema. Emphysema is the destruction of septal tissue, leading to enlarged airspaces and reduced surface area.
CS exposure induces a chronic inflammatory response composed of innate immune cells, predominantly neutrophils and macrophages, and T and B lymphocytes of the adaptive arm. Crucially, the numbers of adaptive immune cells are increased in both the airways and parenchyma of patients with COPD correlating with disease severity. Then importantly, these immune cells infiltrating the COPD lung are organized into tertiary lymphoid structures called inducible bronchus-associated lymphoid tissue (iBALT), which are observed during lung tissue destruction (emphysema).
What will you be working on?
In our recent study published in Nature (2020), we demonstrated that the blockade of lymphotoxin signalling not only resolved iBALT formation but induced regeneration of lung tissue by re-activating endogenous WNT/β-catenin developmental pathways in alveolar epithelial cells and reversed disease progression. Emphasizing that LTβR-signalling is not only crucial for tertiary lymphoid structure formation but direct signalling of epithelial cells contributes to cell death and blockade of regeneration potential in the lung. We have now generated a series of antibodies to target lymphotoxin signalling that we wish to test in human alveolar epithelial cells.
What techniques will you use?
This project will utilize in vitro cell culture assays of human cell lines. Conventional molecular biological methods (qPCR, western blotting) will be carried out in addition to more specialized methods like flow cytometry. This project will be both stimulating and rewarding for anyone with an interest in lung biology or a general desire to target the molecular mechanisms underlying disease pathogenesis.