Project No.2262

Primary Supervisor

Dr Yihua Wang – University of Southampton

Co-Supervisor(s)

Dr Andrea Bucchi – University of Portsmouth

Dr Mark Jones – University of Southampton

Summary

The extracellular matrix (ECM) is like a support network made of proteins that surrounds and holds cells together in tissues throughout the body.

It not only gives tissues their structure and strength but also helps control how cells behave. The ECM is constantly being rebuilt and remodeled, which is crucial for normal things like development, healing wounds, and keeping organs healthy. However, if this remodeling process goes out of control, it can lead to serious diseases like organ fibrosis (scarring), where tissues become stiff and scarred.

We’ve discovered that in lung fibrosis, the ECM becomes much stiffer than normal because it contains more of a certain type of collagen usually found in bone. This stiffness makes the fibrosis worse. Our research shows that this happens because a key cell pathway called HIF (Hypoxia-Inducible Factor) becomes overly active, even when there’s enough oxygen—a situation we call “pseudohypoxia.” This overactivity happens when another protein, called Factor Inhibiting HIF (FIH), loses its function.

Importantly, we found that when the HIF pathway is overactive, patients with lung fibrosis are more likely to have worse outcomes, regardless of how severe their lung function is. We believe that losing FIH activity creates this harmful pseudohypoxic state, leading to continuous scarring and stiffening of lung tissue.

In this project, we aim to better understand this process by:

1. Studying how lung cells change at the gene level when FIH is removed.
2. Identifying specific biological and molecular changes caused by FIH loss.
3. Exploring how losing FIH affects the balance and structure of the ECM.

Ultimately, this research will help reveal how FIH controls the remodeling of the ECM and could point to new ways to treat fibrosis.