The COVID-19 pandemic caused by the virus SARS-CoV-2 is the deadliest pandemic of the 21st century. Despite well-documented evidence that COVID-19 vaccines are safe and effective, the exact ways through which the contents of the vaccine are carried from the muscle where they are injected to the lymph nodes where a protective immune response is generated, is not fully understood. COVID-19 vaccines contain a genetic sequence from the virus called mRNA, contained in small lipid particles. We will use cutting-edge techniques to visualize the specific cells in muscle tissue that take up these mRNA-containing particles and their migratory pathway to lymph nodes, which is still unclear. Additionally, we will determine the genes they express at each stage, and identify the immune cells they interact with. Finally, we will assess new mRNA vaccine formulations to determine the most effective formulation that provides protection against SARS-CoV-2. We will start in animal models of disease and establish the necessary groundwork prior to clinical trials with human patients. This research will help us improve the effectiveness of current COVID-19 vaccines and inform development of all mRNA-based vaccines for the future.
Program: Trainee
Leveraging the native TCR with mRNA vaccines to enhance CAR T cell therapy in solid tumours.
The white blood cells known as T cells actively patrol the body for signs of pathogens or cancers, and their behaviour can be redirected to specifically target cancers by engineering them to express a Chimeric Antigen Receptor (CAR). This personalized approach, known as CAR T cell therapy, has shown remarkable success in certain challenging blood cancers. However, CAR T cell effectiveness against solid tumours has been limited. To overcome the barriers to solid tumour treatment, we propose to combine CAR T cell therapy with an mRNA vaccine (as used in the COVID-19 vaccination campaign). Although CAR T cells have a new cancer-specific receptor, they retain their natural receptor (TCR) which the cell normally uses to recognize pathogens and other foreign material. Based on preliminary data from our laboratory, we predict that the vaccine will directly amplify the activity of CAR T cells through this receptor. We will systematically explore various vaccine design elements, including the formulation, the type of protein encoded in the vaccine and the delivery method to identify the most effective combination. Ultimately, we seek to better understand the variables that maximize combination therapy for translation to human use.
A multi-layer genomic analysis to understand the biological basis of corticosteroid-induced AVN in children with cancer: Toward precision health strategies.
The Problem: Avascular necrosis (AVN) is a serious complication of corticosteroid treatment in some children with cancer, causing bone damage and, in severe cases, requiring surgery. It affects quality of life and places additional burdens on families and healthcare systems. Currently, there are no reliable ways to predict or prevent severe AVN.
Overview of the Research: In a study of 972 children with cancer, I identified four genetic variants strongly linked to corticosteroid-induced AVN. This project will explore how these genetic factors influence AVN risk by validating key predictors in 718 additional patients, pinpointing causal variants, and investigating how these genes affect bone cell responses to corticosteroids.
Anticipated Outcome: Development of a genetic test to identify children at high risk for severe AVN.
Potential Impact: A genetic test for AVN risk would allow doctors to personalize treatment plans for children with cancer. Children identified as high-risk could be monitored more closely or given alternative treatments to prevent AVN from developing in the first place. This would significantly reduce the number of children experiencing this painful and debilitating side effect.
Exploring the Role of Granzyme B in Aging-Related Pruritus: Mechanisms and Therapeutic Potential
Itch, or chronic pruritus, is a common condition affecting about 40% of adults aged 65 and older. For many, chronic pruritus can significantly reduce quality of life. For these individuals, existing treatments like systemic or immunosuppressive drugs are often unsafe due to age-related health conditions. A protein called Granzyme B (GzmB), which is active in aging and inflamed skin, has been linked to itch severity, but its exact role in causing itch is still unknown.
This research aims to uncover how GzmB contributes to itch in aging skin. First, we will study the connection between GzmB levels and signs of itch in skin samples from elderly patients with eczema. Next, we will investigate how GzmB affects skin cells, nerves, and immune responses, focusing on pathways that worsen itch. Finally, we will test a promising new topical GzmB-blocking gel treatment, VTI-1002, in experimental models of itch.
By understanding how GzmB causes itch and testing potential treatments, this study could lead to safe, targeted therapies that improve the quality of life for older adults with chronic itch.
Characterizing the effects of cannabis smoking on airway epithelial cell reprogramming
Cannabis is the 2nd most used recreational drug in Canada, with 6 % of Canadians reporting daily use. Despite the known dangers of cigarette smoking to the lungs which involves exposure to inhaled toxins, smoking is the main method of cannabis consumption. The lungs are protected by a cell barrier called the airway epithelium that is damaged with cigarette smoking and can lead to lung disease. Whether this is true for cannabis smoking is unknown. In this study we aim to understand if cannabis smoking damages the airway epithelium and whether it can be reversed. Epithelial cells collected from cannabis smokers will be analyzed to identify any changes that indicate harm to cells. We believe cannabis smoking is toxic to epithelial cells, reducing the protective ability of the airway epithelium and ultimately leading to worse lung outcomes. This damage may be reversed by stopping cannabis smoking, which would restore epithelial cells back to health. Study findings will be presented at international conferences, published in leading journals and importantly, shared with students using in-school initiatives. This work will build on our understanding of how cannabis smoking affects the lungs and may change how people use cannabis.
Origins and consequences of Persistent Low-Level HIV Viremia During Antiretroviral Therapy
Anti-HIV medications stop the virus from replicating in the body, prolonging life and preserving health. But, these medications are not a cure. This is because HIV, like all retroviruses, can persist within cells called “HIV reservoirs”, which can reactivate at any time to produce virus. This is why anti-HIV medications must be taken for life.
While taking anti-HIV medications, some people experience something called “persistent low-level viremia” where HIV levels in blood suddenly become detectable for no obvious reason. Historically, this was attributed to difficulties in taking medication daily, or the development of HIV drug resistance, so doctors would try to resolve it by changing the medications. But, this would often fail to resolve the issue, causing great stress. Recently, a major discovery was made: that persistent-low-level viremia can originate from HIV reservoirs. Namely, these cells can make clonal copies of themselves, which reactivate to produce HIV. But, many questions remain, and these new discoveries also need to be translated into practice. I will study a unique cohort of people living with HIV using cutting-edge techniques to advance our understanding of the HIV reservoir and improve HIV clinical care.
Reducing harms associated with ‘before medically advised’ hospital discharge
About 1 in 30 hospital patients leave the hospital before completing their treatment. These are known as ‘before medically advised’ (BMA) discharges. These patients are at a much higher risk of death, being readmitted to the hospital, or suffering from a drug overdose. Despite these risks, there are no established care guidelines for how to manage these patients, many of whom struggle with addictions and homelessness. To address this, the study will first examine whether the proportion of patients with BMA discharge has increased in Canada over the past 16 years. Next, the study will use data from British Columbia to explore whether proactive follow-up by a physician within 7 days of discharge can help reduce the risk of death, readmission, or overdose, compared to not having any follow-up. The goal is to create better care strategies for these vulnerable patients. The results will be shared with hospital staff, administrators, and the public to improve patient care.
Targeting G Protein-Coupled Receptors to Improve Neurovascular Coupling in Alzheimer’s Disease
Alzheimer’s is a progressive disease that affects many Canadians. It causes problems with memory and thinking due to the insufficient blood supply to the brain. The cause of this poor blood supply is unclear. Therefore, we will study how this occurs in brain cells, by testing the ability of an interesting molecule present in the brain, known as metabotropic glutamate receptor 5 (mGluR5), to reduce blood supply to the brain by attaching to another toxic molecule called tau, which is commonly found in Alzheimer’s brain. We will isolate brain cells from male and female mice and use them to study how tau binds to mGluR5 and affects its function. We will also use mice sick with Alzheimer’s disease to study how this attachment between mGluR5 and tau causes the reduction in blood supply to the brain. We will then test if drugs acting on mGluR5 can correct the poor blood supply. This research will show if drugs acting on mGluR5 could be a promising treatment option for management of Alzheimer’s disease and how this varies between sexes. Findings will be shared via presentations at national and international conferences, with outreach for press releases and social media platforms.
Drug resistant CAR Tregs to promote transplant tolerance
Solid organ transplantation is often the last treatment option for people whose kidneys, liver, lungs, or heart are failing. Unfortunately, the long-term success of organ transplantation is limited by the delicate balance between the risk of organ rejection and the serious side effects caused by anti-rejection drugs. To improve transplant outcomes, we have developed a new treatment approach using engineered immune cells called “CAR Tregs.” In early tests using mice, CAR Tregs have been shown to help extend the life of transplanted skin, and heart. In human transplant patients, CAR Tregs will need to be tested alongside traditional anti-rejection drugs, which work by blocking the normal function of all immune cells, including CAR Tregs. My research aims to engineer CAR Tregs to be resistant to the negative effects of anti-rejection drugs, so they can work together with anti-rejection drugs to better prevent organ rejection while using lower doses of drugs. The findings from my research will inform the design of future CAR Treg clinical trials with the ultimate goal of improving the quality of life for transplant recipients through the reduced need for harmful medications.
ACTIVE: Adding Life to Years in Cognitive Frailty by Preventing Falls and Promoting Cognitive Function
With age, some individuals experience physical frailty and difficulties in their thinking abilities (i.e., cognitive frailty). This increases the risk of falls and dementia, both of which negatively impact one’s ability to function and quality of life. Falls are a major reason why older adults suddenly go from independent living to long-term care. Thus, it is important to find ways to reduce falls and promote cognitive health in cognitively frail older adults.
Past research shows exercise can reduce falls and promote cognitive function in older adults. However, it is not known whether these benefits apply to those with cognitive frailty. To address this knowledge gap, we will conduct a 12-month home-based exercise program, delivered by physical therapists (PTs), in 328 community-dwelling adults aged 70-89 with cognitive frailty and a history of falls. To increase participation and follow through with the home-based exercise program, PTs will work with each older adult to set exercise goals and create action plans.
Given the immense health burden of falls in cognitively frail older adults, our study could have major health benefits and guide future strategies that positively add life to years among those with cognitive frailty.