MICA: Defining Endotypes of Pulmonary Fibrosis by Understanding the Functional Consequences of Known, and Novel, Genetic Associations with Disease

Idiopathic pulmonary fibrosis (IPF) is a progressive lung condition characterised by scarring (fibrosis) of the lungs. This scarring deforms the lungs and reduces the ability of the lungs to take in oxygen, which causes a person to feel breathless and cough. It is not clear why some people develop IPF, but people with IPF often progress quickly to death and there is no cure.

Each year 6000 people in the UK die of IPF, more than deaths from most cancers, and more than ovarian, cervical and thyroid cancers combined. This makes IPF an important disease to research.

It is currently thought that genetic changes in the cells that line the lung (epithelial cells) make them susceptible to injury and scar formation, although, how these genetic changes promote scarring remains unknown. The main feature of lung scarring is that the lungs become small and stiff due to the abnormally high activity of cells that make scar tissue.

There are broadly two types of cell responsible for scar formation: epithelial cells that line the small airways and airsacs of the lung and fibroblasts, that produce the glue that provides the scaffolding for the lung. When the lung is injured epithelial lung cells send signals to fibroblasts asking for more scaffolding to be made to help repair the lung.

However, if the lining cells are genetically reprogrammed to ask the fibroblasts to build excessive of abnormal scaffolding in response to injury it promotes scarring that make the lungs stiff, and contract, making the lungs small.

Mechanical forces that occur when the lung stretches during breathing, or when the lungs become becomes stiff in IPF, are important in the development of fibrosis. In IPF, scarring begins at the edges and bottom of the lungs, areas that are being stretched the most. Our research has shown that a number the genes associated with IPF affects pathways involved when epithelial cells or fibroblasts are stretched.

Furthermore, when fibroblasts grow in stiff surroundings, such as that within a scarred lung, they become even more active and produce more scar tissue. However, how mechanical forces affect cells with genetic changes found in IPF, or how the genetic changes affect the signals the that epithelial cells and fibroblasts send remains unknown. Importantly, whether the genes and cellular signals reflect sub-types of IPF that might respond better, or worse, to the current anti-fibrotic drugs is not known

This programme of work will use a number of distinct but complementary scientific techniques including genetics, cell and molecular biology, and pre-clinical modelling to investigate how the epithelial lining cells and fibroblasts go wrong during the development of lung fibrosis and whether they can be specifically targeted by anti-fibrotic drugs. The programme will focus on a key molecular pathway, the small G protein signalling pathway, which regulates these cells' mechanical properties.

The aim of this project is to understand 1) precisely map the genetic signals we have already observed, and identify new genetic signals so we can accurately manipulate these genes in test tube experiments 2) define how the genetic signals in epithelial lining cells effect RhoA and Rac function and in turn how this alters the chemical messengers generated by these cells 3) understand how genetic signals in fibrblasts of lead to altered RhoA and Rac activity and the effect this has on the fibrotic potential of these cells 4) define whether these abnormalities leads to different effects in these cells in a way that can be exploited to personalise therapy to ensure the right patient gets the right treatment at the right time.

The work will be undertaken by several academic investigators in partnership with Galecto Biotech, Nordic Bioscience and Redex Pharma to give the programme the best chance of leading to a new treatment for IPF.