Multi-modal Discovery of Mechanistic Drivers of Pulmonary Fibrosis

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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. It is known that genetic changes in cells that line the small airways lead to the production of increased mucous which we believe makes the cells that line the airsacs (alveoli) stiffer and unable to respond to injury in a normal way. When the lung is damaged the injured cells die and need to be replaced by new cells that originated from a special type of airsac cell called (an alveolar type 2 cell) however in scarred lung these cells begin to change to the lining cells but get stuck in a transitional state that is neither a specialised nor lining cell which we believe is related to the build up of mucous and increased stiffness of the lung. Research has shown that when lung cells 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 send and the fate that injured epithelial cells undergo remains unknown. Importantly it is possible to change the cell fate through adapting the mechanical forces within the lung is not currently known.This programme of work will use a number of distinct but complementary scientific techniques including genetics, cell and molecular biology, bioinformatics, bioengineering and biophysics to understand these interactions and determine whether we can alter the fate of lung cells and reprogram them by changing the mechanical environment they exist.This study will bring world leading scientist from a wide range of disciplines to try and find new insights to alleviate the suffering from this devastating disease. The programme will focus on a key cellular process which could link the known genetic, molecular, cellular and mechanical faults that are associated with IPF. The aim of this project is to understand 1) whether a process called cellular extrusion by which abnormal, or excess cells are squeezed out of cell layers occurs in the small airsacs of the lung 2) understand how this process is altered in scarred lung and whether it can be changed to promote lung healing 3) understand the environment in which the cells live can affect how they behave 4) use artificial intelligence and deep learning algorithms to both learn from and inform our experiment in aims 1 to 3.