Research

Respiratory research Holy Grail: EndMT as a therapeutic target in lung fibrosis



Can you describe the aim of your research in 15 words or less?

To solve the mysteries of idiopathic pulmonary fibrosis (IPF) and find a potential cure.

What have you discovered in this area so far? 

In my latest study, my team and I employed a comprehensive, size-based classification approach to assess normal and IPF arteries, and we provided data on absolute counts against a cohort of normal healthy controls. In addition, we analysed the thickness of each layer within the arteries and have studied their effects on lung physiological parameters such as FVC, DLCO and smoking history in IPF patients.

Our data implicates that increased deposition of elastin and collagen type I and IV could contribute to the arterial thickness in IPF lungs. This is the first study demonstrating size-based differences in pulmonary arteries in IPF and their detrimental effect on lung physiology. The process of endothelial to mesenchymal transition (EndMT) appears central to these vascular remodelling changes and a novel therapeutic target for this deadly and complex disease.

EndMT occurs when endothelial cells respond to an external insult or an internal pathological condition, transforming themselves into a more aggressive mesenchymal state, causing irreversible vascular damage or fibrosis. Endothelial cells undergoing EndMT lose endothelial characteristics, such as a change in morphology, loss of vascular endothelial cadherins (VE-cadherins), CD31 and Tie1/2 with subsequent increase in mesenchymal proteins such as N-cadherin, fibroblast specific protein-1 or S100A4, fibronectin, vimentin, SM22-α, calponin and α-smooth muscle actin. As a part of the process, the basement membrane underlying endothelial cells gets disrupted, facilitating the migration of cells. This occurs through active proteolytic degradation of basement membrane collagen by matrix metalloproteinases mediated by the transitioning cells.

What is the significance of your study on EndMT as a therapeutic target in IPF? 

This study provides an in-depth understanding of vascular changes that contribute to IPF development. It also provides insight into the mechanism driving pulmonary hypertension which is common in patients with IPF. Therapeutic inhibition of EndMT could help prevent pulmonary fibrosis and pulmonary hypertension. Our work will also provide new avenues for early diagnosis of IPF using liquid biopsy.

How long until your work affects patient care?

We have identified this new mechanism which we believe is central to IPF pathology and provides new avenues for treatment. We intend to learn more about EndMT using cell culture and molecular studies and will try to inhibit this process with different molecules. We are keen to follow this up in animal studies for drug testing and then clinical trials once we have identified an appropriate molecule and determined its efficacy. We are looking at a 5-year time scale but a lot of this depends on future funding.

What aspect of your research excites you the most?

The exciting aspect of my research is it allows me to solve scientific mysteries and then help others understand them, too. My research will allow early screening and diagnosis of IPF patients and, hopefully, provide suitable treatment options which will improve their quality of life.

You recently won an American Thoracic Society international scholarship for your work in IPF. Can you tell me more about that?

I won this scholarship for my study on vasculature changes in IPF and their impact on lung function. I provided evidence that EndMT contributes to vascular alteration and IPF pathogenesis.

It was very exciting to find out about the scholarship as I was the only one to receive this award for IPF research in Australia.

I did this while facing challenges in acquiring IPF tissues for study and limited availability of labs due to COVID lockdown.

My team and I are very thankful to our collaborators in Launceston General Hospital, The Alfred Hospital, Centre for Heart Lung Innovation, St. Paul’s Hospital and University of British Columbia for supporting us and our funding bodies, Lung Foundation Australia and Clifford Craig Foundation. This scholarship has provided me with access to an international platform to present my PhD work and share it with the scientific community. It has also helped me to connect with other researchers in the respiratory field.

What’s your Holy Grail — the one thing you’d like to achieve in your research career? 

My ultimate goal is to uncover key drivers in respiratory diseases such as IPF, COPD, asthma and asthma-COPD overlap syndrome and identify feasible and affordable therapeutic solutions.

What is your biggest research hurdle?

Getting and sustaining research funding is a perennial obstacle in continuous translational research.

Who has inspired you in work or life?

I am inspired by my PhD mentors Dr Sukhwinder Sohal and Dr Mathew Eapen to conduct ethical, clinical research to answer scientific questions and find possible therapeutic options to help patients live a healthy life.

What new hobby have you picked up during COVID?

During COVID, in my free time, I started developing DIY learning toys for my little girl rather than buying expensive stuff to entertain her. This has kept me motivated and engaged as I have to continuously challenge myself to develop new ideas and solutions.

For example, I used cardboard toilet paper tubes to create a system where she could drop a ball and have it roll through multiple tubes; she really loved that. I also stuck plastic tissue covers on a board and hid different animals’ pictures and some family members’ pictures behind them and she used to find it really interesting to open them up and see what was in there.

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