Uncovering the epigenetic face of lung fibrosis for discovery of novel biomarkers and treatments.

This fellowship will springboard the restart of my academic career after transitioning from industry, enabling me to develop an innovative program of work, build the research momentum and bring the lung field into a new area of molecular epigenetics. Thus, it will enable my establishment as a research leader in the emerging field of lung epigenetics. Chronic lung diseases are one of the most pressing healthcare challenges of our generation, with 540 million patients waiting for curative treatments. Thus, we urgently need innovative and interdisciplinary approaches to address this global challenge. My research brings a unique epigenetic perspective to the lung field with the overarching aim to combat lung diseases at their onset before irreversible changes in the lung tissue occur. The link between lung diseases, environmental exposures and epigenetics is well established, however, how epigenetic changes drive lung disease development is unknown. Likewise, it remains unclear whether epigenetic mechanisms can be targeted for the development of novel therapeutic approaches for lung diseases. In this fellowship, I will capitalise on my unique combination of expertise in epigenetics and lung biology to determine how healthy individuals progress to develop lung fibrosis and identify novel targets for future drug development. Idiopathic pulmonary fibrosis (IPF) is an incurable lung disease, where patients experience progressing breathing difficulties due to irreversible scarring of their lungs. 5 million people worldwide currently live with IPF, having a poor quality of life and an average survival of 3 years after diagnosis. Three features contribute to this grim reality: 1) IPF causes are unknown, limiting possibilities for prevention 2) diagnosis is challenging as no tools for early detection are available 3) treatments are limited, have severe side effects and offer no cure. For discovery of novel diagnostic and treatment options, a precise understanding of molecular changes driving disease is required. We know that epigenetic mechanisms control how and when our genes are switched on or off. We also know that epigenetic marks can be altered by environmental exposures causing disease. Excitingly, epigenetic marks can also be manipulated with the potential to cure disease. Thus, epigenetic signalling provides a novel unique angle for understanding how the disease starts and what changes drive its progression. Yet, despite the discovery of some epigenetic changes in IPF, the comprehensive profiling of epigenetic dysregulation in IPF has not been undertaken. In this project, I will employ an unbiased profiling approach to compare global epigenetic signatures of healthy and IPF cells across disease stages and discover epigenetic changes characteristic of early and late disease. I will interrogate the molecular signature of IPF to identify and validate novel candidate markers for disease detection. Importantly, I will then apply our unique epigenetic editing approaches in cell culture to specifically reverse aberrant epigenetic changes and examine their functional relevance. Through this pioneering approach, I will determine which sites may play a causal role in disease, providing the most promising targets for interventions. Finally, I will harness this knowledge to identify novel disease regulators. I am uniquely placed to deliver this ambitious project as I have cross-sector experience in preclinical drug development and in dissecting epigenetic mechanisms of disease. But this fellowship is more than just a scientific project. My unique approach has the potential to transform the way lung epigenetic research is done, benefiting future generations of scientists and patients, and establishing me as a leader in this emerging research field. This fellowship will also enable engagement of the wider community in Wales and UK around respiratory health, creating a real scientific, economic, and social impact.