Holy Grail: The endoplasmic reticulum’s role in severe asthma pathogenesis


20 Oct 2021

Can you sum up the aim of your research in 10 words?  

Understanding disease mechanisms and investigating therapeutic targets for severe asthma.

What led you to this line of research? 

I always loved biology and it was my passion. When I started doing my PhD, I selected respiratory research. I think our lungs are absolutely amazing. They are vital, highly efficient, and beautifully complex in their structure.  And it’s amazing to see the complex interactions in the lung, particularly with our immune system. So, I was really curious to learn more about those things and ended up doing asthma research. As we all know, asthma is a very complex disease and has no cure, although it can be effectively controlled using current medications. Still, severe refractory asthma patients are resistant to current medications and have poor control over their symptoms. So, in my research, I am focusing on understanding disease mechanisms at the cellular level and identifying efficient therapeutic targets for severe asthma.

What aspect of your research excites you the most? 

I really enjoy trying new techniques and learning new things in the lab. Collecting lung stem cells from asthmatic patients and growing them into differentiated 3D cultures in the lab to mimic the asthmatic lung is one of the most fascinating parts of my research. We treat these 3D models with various drugs, allergens, viruses and bacteria and characterise their responses.  In this manner we can better understand how asthmatic lungs behave differently from healthy lungs. These observations lead us to new avenues for research and I think those lab discoveries excite me most.

What have you discovered in this area?  

We have shown that endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) can be involved in the pathogenesis of asthma and in other lung diseases (PMID: 29472925). The ER is an intracellular organelle that is responsible for protein folding and their translocation into secretory pathways. ER dysfunction results in the accumulation of aberrantly folded proteins in ER. Perturbations in ER homeostasis lead to an adaptive response termed the UPR that upregulates compensatory responses to restore homeostasis. These include increasing ER folding chaperones, ER protein degradation and inflammation, and reducing protein translation. If unresolved, cell death ensues. We found that ER stress is heightened in severe asthma patient samples and correlates with poorer lung function. We also found that ER stress is correlated with eosinophilic and neutrophilic inflammation which could be a treatable trait in severe asthma (PMID: 34510013).

How long before your work might impact patient care?

We are still at the pre-clinical level. With our current research findings, we know that an upregulated ER stress signature is present in severe asthma patients (PMID: 34510013). We have also found that reducing ER stress using FDA-approved drugs can effectively reduce airway remodelling and inflammation in our pre-clinical models of asthma (unpublished data). Using our steroid-resistant asthma murine models, we showed these treatments are effective in reducing airway hyper-responsiveness and inflammation, whereas steroids did not (unpublished data). Collectively, our findings show that inhibiting ER stress could be a promising treatment for certain phenotypes of severe asthma. However, we believe we need more pre-clinical research before proceeding into clinical trials and patient care. Fortunately, we have received an NHMRC ideas grant (2020/2021) to continue our pre-clinical research and further investigate the importance of ER stress in the pathogenesis of asthma.

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

I want to be a world-renowned research scientist in the area of respiratory medicine and do world-class medical research, making new discoveries and finding novel therapeutics for asthma. I want to see every person with asthma getting the right treatment which would help them live a full and normal life.

What is your biggest research hurdle? 

I believe in general, the biggest research hurdle in Australia is very competitive funding in medical research. Although we have great ideas, skills and potential, the inadequacy of research funding limits us from doing great research. Most researchers feel insecure about their jobs and research funding. I feel the same. I think the government should allocate more funding towards medical research as it is a vital part of our community, the significance of which we are particularly feeling today in the current pandemic.

Who has inspired you in work or life?  

Many people have inspired me in my life, but I would say the most important person has been my mother. She is the greatest role model in my life. She is a great woman who has always demonstrated tremendous courage and leadership and she always works with great positivity. I think that influenced me to build up my personality, skills and become who I am today.

Also, my supervisor Professor Peter Wark has always provided immense support and great freedom in my research which I appreciate, and this has helped me to grow in my career.

What new hobby have you picked up during COVID? 

I think these days I tend to do more gardening. I really enjoy it and it allows me to interact with my family and spend more time with them. My favourite thing about it is that it makes me so happy, especially when I pick my fruits and vegetables from our own backyard. I think gardening helps me to relax, calm down and have a good work-life balance.

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