Coxsackie virus B (CVB) is the number one cause of viral heart inflammation leading to heart failure and sudden death in ~20 percent of infected children and young adults. In most people, CVB infection causes mild symptoms. However, individuals with underdeveloped and/or compromised immune systems are at increased risk of severe disease. Normally, our healthy immune system acts as a first line of defense against viruses, but excessive and sustained activation of our immune system can be harmful, leading to chronic inflammation and injuries to the heart. The objective of my project is to study how CVB hijacks a novel immune pathway called cGAS-STING, to trigger harmful inflammation in the heart. Our knowledge gap is that we do not completely understand how CVB hijacks the cGAS-STING immune pathway and whether blocking this pathway with drugs can protect the heart. To accomplish this goal, we will precisely identify which cells and immune pathways are responsible for harmful inflammation of the heart. Findings from this study have the potential to open new therapeutic avenues to combat existing and emerging viral threats.
Award Partner: Centre for Heart Lung Innovation
Understanding the link between lung genomics, transcriptomics, and sex differences in COPD
Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease that causes respiratory symptoms such as shortness of breath and is the fourth leading cause of death worldwide. While COPD affects both males and females, females, in general, have worse symptoms and more COPD complications compared to males. We still do not have a good understanding as to why COPD behaves differently in females versus males. COPD was thought to mainly affect elderly males who were cigarette smokers; thus, most of the research have focused on males rather than females. To shrink this gap in knowledge, it is necessary to include females in biomedical and clinical studies and investigate the biological reasons behind why sex might affect how COPD develops. We hypothesise that some of the genes associated with COPD have different effects on males and females. In this project we will use a patient’s genetic code and how their genes behave to determine sex-specific signatures in their lungs and airways, and then measure how these signatures can predict the development of future COPD. This project can potentially contribute to the improvement of COPD treatment (particularly in females) and to identify new therapeutic targets for COPD.
Ventilation heterogeneity in asthma, COPD and asthma-COPD overlap: oscillometry and pulmonary MRI
Airways disease is a hallmark finding in both asthma and chronic obstructive pulmonary disease (COPD). Although tobacco cigarette smoking is the largest known cause of COPD, recent studies have revealed that 10% of patients with life-long asthma may develop COPD later in life without ever smoking. The mechanisms underlying asthma transition to COPD are unknown. To better understand this transition, this proposal will use 129Xe magnetic resonance imaging (MRI), computed tomography (CT) imaging and oscillometry to measure airway abnormalities in patients with asthma, COPD, and asthma-COPD overlap. These measurements will provide a better understanding of airway abnormalities that contribute to development of COPD in these patients with asthma. COPD is the most common cause of hospital admission in Canada and treatment costs in BC alone are estimated to be over $600M/year. The results generated from this proposal may identify new ways to treat COPD or halt its development in patient with asthma, contributing to reduced hospital admissions and costs related to COPD.
End of Award Update – March 2024
Results
With the emergence of long COVID, we pivoted our novel lung imaging methods to investigate the lungs of people who experienced COVID-19 infection with persisting, long term symptoms over 1-year after infection. In collaboration with colleagues at the University of Kansas Medical Center and Duke University, we created a multi-centre dataset of patients with long COVID to better understand how long COVID may differ across different patients. We used xenon gas magnetic resonance imaging (MRI) to measure how effectively the lungs of patients with long COVID were performing gas exchange (the main function of the lungs). Our results showed that there are 4 different sub-types of long COVID that have different lung abnormalities. We anticipate that the xenon MRI results can be used to help determine appropriate treatment for patients experiencing long COVID.
Impact
In our centre, the xenon MRI results have been used to help determine appropriate for different patients with long COVID. Our results uncover the lung-specific abnormalities that are related to long COVID.
Potential Influence
We anticipate these results will help to better understand and classify patients with long COVID, towards appropriate treatment and alleviating patient symptoms.
Next Steps
We are using similar xenon MRI methods to investigate other forms of lung exposures including cigarette smoking, cannabis smoking, and vaping.
Useful Links
https://erj.ersjournals.com/content/early/2024/02/02/13993003.02301-2023
Connecting clinical research and economic evaluation by mapping lung function to EQ-5D-5L in patients with interstitial lung disease
Interstitial lung disease (ILD) is a group of diseases that cause inflammation and scarring of the lungs. It is important to identify ways to improve quality of life (QoL) for patients living with this chronic condition. This research will explore how QoL changes over time in ILD and identify factors that can potentially be modified to improve QoL.
Mycophenolate mofetil (MMF) and azathioprine (AZA) are two common medications used to treat certain ILDs and improve QoL. Despite MMF being better tolerated, only AZA is initially covered by PharmaCare in BC. This research will determine whether MMF is more cost-effective than AZA and could inform drug reimbursement policies.
Economic evaluations are used by funding agencies in Canada to determine whether a drug should be funded or not. However, economic evaluations for ILD drugs are limited because clinical trials do not provide the required information. This research will create an algorithm that allows economic evaluations to be completed even when these required data are not available. These economic evaluations can then be used to guide decisions on funding effective treatments in ILD.
The effects of 60% oxygen during exercise training in patients with fibrotic interstitial lung disease
Breathing discomfort is common in patients with interstitial lung disease (ILD) and often results in an inability to perform physical activity, leading to a poor quality of life. Exercise training can reduce breathing discomfort and enable ILD patients to perform physical activity. However, severe breathing discomfort makes it challenging for these patients to withstand the amount of training they need to get the most benefit. A recent study showed that ILD patients breathing supplemental oxygen had less breathing discomfort and were able to exercise for longer compared to breathing room air. Another study showed that breathing supplemental oxygen was safe for patients with ILD for a single exercise session. However, we still do not know if these findings can be applied to a long-term exercise program.
Therefore, the purpose of this study is to determine if using a higher amount of oxygen during a rehabilitation program is a safe intervention that translates to greater benefits from training compared to the same regimen without the additional oxygen. We are also interested in examining if higher intensity training sessions with added oxygen affects every day physical activity levels.
Structural valve degeneration in bioprosthetic heart valves
Bioprosthetic heart valves (BPHVs), valves made of biologic tissues rather than synthetic materials, have revolutionized the treatment of heart valve disease, which constitutes a significant health and economic burden in BC, Canada and around the world. BPHVs serve as an alternative to mechanical valves, which require lifelong treatment to prevent clotting and therefore lead to an increased risk of bleeding.
With the development of new transcatheter methods for delivery of BPHVs, they now represent the overwhelming majority of valves. Despite these successes, the long-term durability of BPHVs is not well established and remains a concerning potential limitation.
Dr. Sellers’ research will look to determine how BPHVs degenerate and potential strategies to assess this in patients. This will include using a combination of analysis of dysfunctional valves and novel imaging approaches using computed tomography (CT) imaging.
The results of this research will help determine the long-term durability of BPHVs and improve decision-making for patients with heart valve disease.