Sepsis is a serious and life-threatening condition that arises from infections. Although medical advances have reduced the mortality rates of sepsis, many survivors have a weakened immune system and are at a higher risk for subsequent infections. Exercise represents a powerful tool to recover the immune system and reduce post-sepsis hospitalization. Through my research, I will explore how exercise impacts the immune system of sepsis survivors by specifically investigating immune cells called myeloid cells, which become dysfunctional following sepsis. Initial results in a mouse model of sepsis have found that four weeks of exercise improves survival to a subsequent lung infection due, in part, to restoration of immune system function and that female mice respond differently to sepsis than male mice. To understand this better, I will investigate how exercise changes immune cells and differences between sexes. In collaboration with an ongoing clinical trial in sepsis survivors, I will explore whether molecular changes in immune cells are present in human patients. Overall, my proposed research will lead to more effective exercise treatments for sepsis survivors to improve their quality of life and return back to health.
Research Pillar: Biomedical Research
Unraveling the immunotherapy obesity paradox in triple-negative breast cancer
Breast cancer is the most common cancer in women. Triple-negative breast cancer (TNBC) is particularly difficult to treat due to a lack of typical treatment targets. Obesity is linked to higher incidence of TNBC and worse cancer progression; as obesity rates rise, it is important to consider the effects of obesity on TNBC.
Cancer cells evade the immune system by deactivating immune cells. Anti-PD-1 drugs restore immune response against tumours, but most patients do not experience a benefit. Paradoxically, recent research suggests that obesity enhances anti-PD-1 therapy.
We will investigate the effects of obesity on lipid utilization in TNBC tumour and immune cells and anti-PD-1 effectiveness. We hypothesize that obesity will enhance anti-PD-1 and studying changes in lipid usage in tumour and immune cells will reveal mechanisms responsible for increased anti-PD-1 effectiveness. Mice will be fed a regular or high-fat diet and implanted with TNBC cells into mammary fat tissue. We will compare lipid profiles in the tumour and immune cells of lean versus obese mice and evaluate anti-PD-1 efficacy. By studying how obesity alters lipid metabolism in TNBC, we will uncover mechanisms responsible for modulating anti-PD-1 effectiveness.
Mapping and Enhancing mRNA Vaccine Delivery & Immune Activation for SARS-CoV-2
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.
Investigating gene-edited CAR T cells as an effective therapy in cancer
Large B cell lymphoma (LBCL) is the most common type of non-Hodgkin lymphoma and causes a significant health burden. Cell-based therapies, including chimeric antigen receptor (CAR) T cells, have had great success treating B cell cancers, with about half of patients with lymphoma experience long-term clinical benefit. However, treatment of LBCL in individuals displaying significant extranodal disease (cancer presenting in peripheral tissues rather than/or in addition to lymph nodes) has been unfavourable and existing therapy must be improved. Thus, we have used a screening technique to identify genetic modifications that may promote CAR T cell functions in these difficult-to-treat sites. Candidate genes will be increased or blocked to produce more effective immunotherapy. CAR T cells harboring these beneficial gene modifications will be produced and their functional capacity assessed using culture-based assays. The modified CAR T cells will then be tested in mouse models of lymphoma to determine whether they have an enhanced ability to treat disease. The current study uses an innovative and unbiased method for discovery of targeted gene modifications that may be used in CAR T cell therapy to better treat extranodal B cell lymphoma.
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.
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.
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.
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.
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.
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.