Respiratory Syncytial Virus (RSV) is the number one cause of hospitalizations and death for severe respiratory infections in young infants across the world. Antibodies made by our immune system are important to help fight viruses like RSV. Newborns lack their own antibodies at birth and rather obtain them from their mothers during pregnancy. To increase antibody levels at birth in babies, researchers have proposed to vaccinate mothers against RSV during pregnancy. We do not completely understand how much antibodies are critical for protection against RSV infection in early life. We also do not know which function(s) of RSV antibodies are associated with protection from RSV disease in young infants. Infants’ samples obtained at delivery will be tested for levels and different functions of RSV antibodies and this will be correlated with the risk of infection in infants. Data from these projects will inform RSV vaccine design and development, especially in pregnancy as the levels and functions of RSV antibodies after vaccination should be similar to the levels and functions that protects from RSV disease.
Research Pillar: Biomedical
Development of a non-invasive diagnostic to detect bacterial pulmonary infections in patients with cystic fibrosis
Cystic fibrosis (CF), once known as an untreatable fatal disease in early childhood, is now recognized as a fairly manageable disease but with a primary morbidity dominated by persistent lung infections. Our team and others have shown that bacterial volatile molecules in human breath represent a substantive diagnostic potential for lung infections. The focus of almost all breath research in CF, including ours, has been on two bacterial pathogens (Pseudomonas aeruginosa and Staphylococcus aureus). Here, we propose to target three additional pathogens (Haemophilus influenza, Stenotrophomonas maltophilia, and Burkholderia cepacia complex) that are common for patients with CF and are also broadly relevant to pneumonia in children. My scientific approach spans the careful testing of the molecules produced by bacterial cultures as well as breath of patients with CF. The expected outcomes (biomarker signatures) will provide clinical utility in the diagnosis of these pathogens as well as monitoring antimicrobial therapy efficacy. In addition, the signatures will likely provide a greater understanding of pathogen metabolism.
Portable MRI for multiple sclerosis: Feasibility establishment and technical development for clinical and research applications
Magnetic resonance imaging (MRI) is an important tool for diagnosing and monitoring multiple sclerosis (MS), a disease which affects millions of people. Unfortunately, current clinical MRI scanners are expensive to purchase and operate, have long wait times, and are often inaccessible for people in remote areas or with mobility issues. Recently, the world’s first portable and easy-to-use MRI scanner was developed by a commercial company (Hyperfine), and it will be available at the UBC MRI Research Centre in early 2021. Because this portable MRI scanner has a very low magnetic field and a small size, it has few safety concerns and can be easily brought to people anywhere. This platform will vastly improve MRI accessibility for clinical use, and make large-scale MS research possible. However, the portable MRI scanner’s ability to detect MS lesions in the brain needs to be tested. My project will compare the portable MRI scans with standard clinical MRI scans in terms of image quality for MS brains, and come up with a guideline for the use of portable MRI in MS. This work will be the first application of portable MRI to MS clinical care and research, and the ultimate goal is to bring MRI technology to everyone with equal opportunity.
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.
The impact of the loss-of-function ankyrin-B p.S646F variant on cardiomyocyte and neuronal excitability: Implications for diagnosis and treatment of heart disease
The electrical rhythms underlying heart and brain function are sustained by proteins that form pores in cellular membranes that flux ions like calcium and sodium. These pores are anchored in place by a molecule called ankyrin-B (ANKB). We discovered a genetic change in the Gitxsan Nation of Norther BC that results in a version of ANKB (ANKB p.S646F) associated with heart defects at birth, arrhythmias, sudden death, seizures, and cerebral aneurysms. We showed that this version of the ANKB molecule is mishandled by immature heart cells; however, we do not fully understand how this ANKB version contributes to clinical manifestations. As a clinician-scientist and expert in microscopy-based measurement of cellular excitability, I am well-positioned to bridge this important knowledge gap. By imaging calcium and voltage changes in living cells, I will study the impact of partial loss of ANKB and expression of disease-associated ANKB p.S646F versions on heart and brain cell excitability. I will also compare heart cell excitability data with patient electrocardiograms to help understand the connections between fundamental laboratory and clinical observations.
Investigating the role of sleep disruption in the progressive memory loss associated with Alzheimer’s disease
Alzheimer’s disease is the most common cause of dementia and a leading cause of death in Canada. Unfortunately, there are currently limited treatments available for this devastating disease. Recently sleep has been shown to regulate important aspects of Alzheimer’s disease pathology and is emerging as a promising target for novel interventions to prevent and slow disease progression.
To identify how changes in sleep and the body’s biological clock contribute to the cognitive deficits associated with Alzheimer’s disease, we will conduct a combination of preclinical experiments to evaluate causal mechanisms and clinical studies to evaluate the same processes in patients diagnosed with Alzheimer’s disease.
The ultimate goal is to determine whether treating specific aspects of sleep disruption is an effective therapy for Alzheimer’s disease, which will help identify new treatments to prevent the progressive memory loss, improve the health and quality of life of patients and their families, and reduce the economic burden of the disease.
AI-driven integration of omics and histopathology for biomarker discovery in cancer
Tumors of the same cell type, origin, and stage have unique genetic features that impact course of disease and treatment response. However, management of cancer is still largely dictated by a patient’s tumor cell type and stage without further refinement.
We intend to take advantage of the unique opportunities afforded by BC’s cancer care system (with a single payer system and uniform treatment protocols, together with high quality patient outcome data) to build an artificial intelligence (AI)-based cancer biomarker discovery platform. The proposed platform will integrate the images of the tumor tissues along with their genetic markers through AI to identify novel biomarkers for cancer patient risk stratification and management. Our program will:
- Improve efficiency in pathology laboratories.
- Identify tissue image features that correlate with tumor genetics which can rapidly and accurately classify patients into clinically relevant groups.
- Generate new biomarkers for precision medicine by combining tumor genetics and tissue imaging.
Ultimately, this program will improve patient outcomes, alleviate the need to perform expensive genetic profiling tests, and lead to significant cost-savings in the healthcare system.
Molecular mechanisms of sensing and repairing dysfunctional mitochondria
Mitochondria are factories in our cells that produce energy and building blocks. Constant delivery of proteins, the factory “workers”, to mitochondria from other parts of the cell is important for proper function of these factories. Defects in delivery occurs in many diseases, including diseases involving nerve cell death (neurodegenerative) like Alzheimer’s. It is thus extremely important and timely to gain more knowledge on how cell health is maintained when protein delivery into mitochondria is damaged.
I discovered a new mechanism, the mitochondrial compromised protein import response (mitoCPR), which protects mitochondria and cells when protein delivery is damaged. I showed that such damage leads to proteins getting stuck and clogging entry sites into mitochondria. My research aims to gain a deeper understanding of how the mitoCPR unclogs mitochondria entry sites and helps them recover under disease and physiological conditions. Using molecular biology and advanced technologies such as gene editing, proteomics, and microscopy, my lab will reveal how the cell keeps mitochondria healthy. This research may uncover new treatment strategies for neurodegenerative and other diseases, caused by improper mitochondrial function.
Unlocking the competitive potential of pluripotent stem cells: Towards novel stem cell therapeutics
Pluripotent stem cells (PSCs) have the ability to expand endlessly, making copies of themselves, as well as to differentiate into all specialized cell types of the body. As a result, PSCs have opened the door to deriving cellular therapies that have unprecedented promise for treating degenerative diseases. Despite this promise, we lack an understanding of how to control their behaviour — whether they divide, die, or differentiate.
My laboratory will use a combination of cutting-edge experimental and computational technologies to study PSC fitness — the ability of these cells to eliminate each other via cell-cell killing. Our research will uncover the genetic basis of their fitness to predict the emergence of abnormally competitive PSCs, those with aberrant genetic mutations, and to use synthetic biology tools to remove these from cell manufacturing batches. We will also engineer PSCs to enhance their fitness, allowing us to grow these cells in the lab with better efficiency and safety. This research will lead to health and economic benefits for Canadians, improving the efficacy of cell therapies and building on our legacy of stem cell research that began with the initial discovery of stem cells in 1961 by Drs. Till and McCulloch.
Developing patient-specific technologies to improve functional outcomes following joint replacement
The inability of patients to perform daily tasks after joint replacement remains a significant challenge as well as a burden on health systems because these poor results often require additional treatment (e.g. rehabilitation) and re-replacement. This challenge can be addressed by surgeons using individual patient characteristics to personalize how they perform joint replacement surgery. However, many surgeons perform too few procedures to effectively personalize their plans and thus technologies are needed to provide assistance.
The goal of this research is to develop an improved understanding of how patient specific factors affect the results of joint replacement as well as to develop technologies that can collect data about each patient’s individual characteristics and use these data to assist surgeons in optimally planning each surgery. This will be achieved by a combination of computer-based biomechanical research, statistical modelling, and novel sensor development. This work will improve our understanding of personalized joint replacement, yield new clinical technologies, enable surgeons to more effectively personalize surgery, result in improved patient function, and improve the health systems in BC and beyond.