Role of AXL kinase in Human Idiopathic Pulmonary Fibrosis
Research type
Research Study
Full title
Elucidating the role of AXL signaling in Idiopathic Pulmonary fibrosis utilising human primary small airway epithelial cells
IRAS ID
344429
Contact name
Stephen Ward
Contact email
Sponsor organisation
University of Bath
Duration of Study in the UK
0 years, 4 months, 31 days
Research summary
Idiopathic pulmonary fibrosis (IPF) is a serious chronic disease that affects the tissue surrounding the air sacs in the lungs. This condition develops when lung tissue becomes thick and stiff for unknown reasons. It has unclear origins, a low survival rate and occurs in most part, in patients with advanced age and has an unmet medical need. Normally, “epithelial” cells line the air sacs which, under conditions of stress/damage to the lung, transform into cells called myofibroblasts. These produce excessive levels of components of the extracellular matrix such as collagen. Normally, repair mechanisms can normally lead to epithelial cell barrier repair/regeneration, but sometimes (as in IPF), the repair process is overwhelmed and a 'fibrotic scar' forms over the damaged area, leading to accumulation of stiff fibrotic tissue and loss of lung function.
This project wil explore the intracellular biochemical mechanisms by which lung repair mechanisms become dysregulated in IPF, focusing on a molecule called Axl, which is increased on the surface of epithelial cells in mouse lung injury models. Axl elicits intracellular biochemical events upon engagement with a partner molecule “GAS6” which is produced by neighbouring cells. Gas6 is promiscuous and can also partner with two Axl cousins (TYRO3 and MERTK). Another molecule “Pros1” binds these cousins, but not Axl itself. However, we observed an increase in Pros1 levels in mouse lung tissue following injury, but a decrease in Gas6. Moreover, advanced high-resolution microscopy, revealed a physical interaction between Axl-Pros and biochemical signals elicited by Axl activation. This suggests that drug targeting of Axl/Pros- interactions could provide a novel therapeutic intervention for IPF. We therefore wish to explore the functional states as opposed to just the levels of Axl, Gas6, and Pros 6 in IPF human IPF to truly understand their interaction and how these impact the disease state.
REC name
London - Surrey Research Ethics Committee
REC reference
24/PR/1158
Date of REC Opinion
17 Sep 2024
REC opinion
Favourable Opinion