Our aim is to exploit the parallels between lung development and disease to understand the pathobiology of lung disease and develop novel regenerative/repair strategies to treat them.
Respiratory diseases are a significant cause of morbidity and mortality worldwide, however, effective treatments for many respiratory diseases are limited. At the same time, certain medical interventions aimed at prolonging life, such as mechanical ventilation, can cause injury to the lungs which may lead to acute damage or long-term structural changes.
Our group seeks to understand how developmental, environmental or medical factors contribute to adult lung disease and/or injury and ultimately to discover novel treatments to repair or induce regeneration of the lungs.
Role of developmental genes in adult lung disease and tissue repair
Our recent work on the Wnt/PCP pathway has shown that this pathway also plays a key role in adult lung homeostasis and repair (Poobalasingam et al. 2016).
1) We are investigating how we can manipulate the PCP pathway to modify lung repair.
2) We also study the function of other genes that we have shown are important for lung development in adult lung homeostasis and disease e.g. see aim 2 in current research.
3) We are working on elucidating the most effective ‘lung repair cocktail’ .
Imaging lung development, injury and repair
We have previously used real-time imaging to enable us to discover details about the role of genes in lung development that would not have been possible using 2D/static imaging techniques.
We have established Precision-cut lung slice models from human and mouse tissue, future work will continue to use this important pre-clinical tool.
1) Real-time modelling of lung injury in slices.
We use this system to assess potential novel treatments to manipulate lung repair.
2) Stretch of lung slices
We are exploring this model for studies in lung mechanobiology.
3) Real-time imaging of alveolarization
In this video extensive movement of epithelial cells (labelled green) can be seen. The red arrows indicate live septation where a single airspace is sub-divided by cell migration across the space to create two new airspaces (see a1-a2 and a3-a4). This increases the surface area available for gas exchange. In addition clustering of epithelial cells into a compact area can be seen within the areas outlined by blue circles.
Alveoli, the gas-exchanging compartment of the lungs, are thought to form by cells repeatedly sub-dividing airspaces eventually creating the large surface area needed for respiration. Despite their critical function, current knowledge is based solely on 2D pictures. We have used live 3D imaging of alveolarization in slices to determine precisely how alveoli form (Akram et al 2019).
Bioinformatics approaches to identifying disease associated genes
1) Through collaboration with Peter Burney (respiratory epidemiologist) and Cosetta Minelli (medical statistician) at NHLI we are using existing databases to identify novel lung disease associated genes. (Minelli et al. 2016).
2) Using a gene driven approach, we are interrogating existing databases to see whether any genomic changes in our genes of interest, identified from our mechanistic, wet-lab studies are associated with altered lung function in the human population. We have successfully done this for the VANGL2 gene (Poobalasingam et al. 2016).
3) Using UK Biobank data, we are investigating how interactions between dietary factors and genes important for lung development modify lung function.
Mouse models of lung disease susceptibility genes
We are investigating both point mutants and null mutants of human lung disease associated genes in the mouse. This work will enable us to confirm the identity of candidate disease susceptibility genes identified in human studies and to understand the function of these genes.