Year: 2021

Despite significant advances in the treatment of many cancers, ovarian cancer still claims hundreds of lives in Canada every year. A molecule called podocalyxin is “switched on” by a high percentage of tumors from various cancer types including ovarian cancer and its expression is associated with poor prognosis. Since the immune system has a key influence in the control of tumor growth, one of my objectives will be to study how podocalyxin influences the immune response against tumors.
In addition, Dr. McNagny’s team recently developed an antibody, called PODO447, which recognizes an exquisitely tumor-specific form of podocalyxin. Accordingly, my second objective will be to explore the use of this antibody as a method to either attract immune cells to cancer cells and kill them or as a tool to deliver toxins and chemotherapeutic agents specifically to tumor cells while sparing normal tissue. Preliminary experiments in animal models already are suggesting the efficacy of the latter approach. In conclusion, the results obtained in this project will allow us to take one more step toward the objective of ultimately treating ovarian cancer patients with the podocalyxin targeting therapies.

Meningitis is a serious inflammation of the lining surrounding the brain and spinal cord, caused by viral or bacterial infections. One in ten people who develop meningitis will die, and 20% will experience serious, lifelong consequences, such as hearing loss or brain damage. The World Health Organization (WHO) has called for full prevention and control of this disease by 2030. Our team is collaborating with the WHO to develop evidence-based immunization strategies for this initiative. My research project will pool data from all previous vaccine studies on meningococcal group B (MenB), to assess the safety and protective effect of different MenB vaccines. Our goal is to use that data to answer questions such as, “How safe current meningococcal group B vaccines are?”; “How long they can protect us from getting the disease?”, and “How many doses are needed and on which schedule?”. Findings from this research will guide WHO strategies on dosing and timing of vaccines, to eradicate meningitis by 2030.

Postpartum depression is common, affecting 10-15% of women, and increases risk for suicide. Postpartum psychosis is rarer (approximately 1/1000 women), but is a psychiatric emergency. Women with postpartum psychosis or severe postpartum depression need care in hospital to protect their health, and the health of their families. Currently in Canada, these hospital stays separate women from their babies, which can be traumatic for mother and baby. In other countries, Mother-Baby Psychiatric Units (MBUs) admit both mother and infant for care. This study will investigate whether MBUs are suitable for Canada, or whether another model of care would be better for Canadian families. To do this, we will conduct three sub-studies. Sub-study 1 will amplify women’s stories of the experience of a hospital stay for postpartum mental illness in Canada. Sub-study 2 will describe the frequency and predictors of hospitalization for postpartum mental illness. Sub-study 3 will provide a rich picture of the MBU model of care through a case study of five international MBUs. By understanding how to best meet the needs of women and families living with serious postpartum mental illness, we aim to improve mental health outcomes across generations.

The rhythmic beating of the heart requires coordinated electrical activity that causes the heart to contract and relax. The electrical activity is controlled by proteins in the membranes of heart cells that form ion channels. Failure of channels to work properly is associated with abnormal heart rhythm, heart attack and sudden death. Long QT Syndrome (LQTS) is a condition that affects 1:2000 people and often results from inherited mutations in one of the heart channels. However, determining whether a mutation will cause the individual serious heart problems is still a major challenge. By using cutting edge technology, like induced pluripotent stem cells and CRISPR, we can recreate patient mutations in cells in the lab and turn them into beating heart cells. Specific techniques can be used to look at individual heart cells, as well as heart cells in a layer that beat together. The properties of the cells can be measured so that the effects of the mutations can be understood, and so that newer specific drugs can be tested to see if they are effective against different mutation types. The results from this research will help inform clinicians on how to better help patients with LQTS and potentially identify new, better treatments.

Spinal cord injuries (SCIs) are becoming more prevalent in older adults, and the number of older adults is rapidly increasing. This is a challenge for healthcare professionals because the existing health issues and poor health of older adults may limit invasive surgical treatments. The most common form of SCI seen in older adults is caused by the neck extending beyond its typical range, damaging the spinal cord in a pattern that is different pattern than what is seen in younger adults. It is known that the risk of spinal cord injury and observed tissue damage is worsened by age-related degeneration in the spine; however, there is limited understanding of how these degenerative changes alter tissue damage caused by an SCI. The proposed study will consist of three objectives: (1) to measure the type and amount of degeneration typically found in older adults, (2) to simulate the spinal cord injury and use it to predict how tissue will be damaged (3) to predict how the tissue damage changes when the model includes spinal degeneration.

The immune system is critical for fighting infections but left unchecked, can attack healthy tissues resulting in autoimmunity or transplant rejection. Regulatory T cells (Tregs) are the immune cells responsible for controlling immune responses, so Treg transfusions are being investigated as treatments for these conditions. Unlike immunosuppressive drugs, Tregs are customisable and can have long-lasting effects.

Tailoring Tregs to treat specific diseases typically involves genetically modifying the cells. One approach involves incorporating synthetic proteins called chimeric antigen receptors (CARs) to help the Tregs migrate to where they are required in the body and specifically suppress harmful targets. I will build on this approach and explore the potential of using novel precise gene editing techniques (CRISPR) to maximise the survival and function of CAR Tregs following infusion.

This work will inform ongoing clinical studies that are investigating CAR Treg therapy in kidney transplantation, as well as future studies with other diseases. Fine-tuning personalised Treg therapy is key for its wide-scale implementation and potential to transform the life quality of autoimmune disease patients and transplant recipients.

Problem: Many older adults experience prolonged bed rest as a result of injury, surgery, or hospitalization and this may have detrimental effects on both their cognitive (i.e. thinking) and physical abilities. Ensuring older adults engage in daily exercise during bed rest may counteract the negative consequences of physical inactivity on cognitive abilities.
Research Overview: Maximizing on an opportunity provided by CIHR and the Canadian Space Agency, we will determine: 1) the effects of 14 days of bed rest on cognitive function in adults aged 55 to 65; 2) the impact of daily sessions of physical exercise in counteracting the effects of bed rest on cognitive function; 3) the mechanisms (i.e. how) by which bed rest and impacts cognitive function and its influencing factors (e.g. sex). Participants will be randomized to a group with either 14 days of bed rest with three physical exercise daily sessions (total of 60 minutes) or a control group (bed rest only).
Potential Impact: Promote the development of novel interventions and rehabilitation strategies to counter the adverse effects of physical inactivity, including bed rest, on cognitive health in older adults during transitions in care.

Chronic low-grade inflammation (i.e. the persistent low-level production of pro-inflammatory factors by immune cells) is a major contributor to the development and progression of type 2 diabetes (T2D). We have recently demonstrated that cells from individuals with T2D also have impaired anti-inflammatory responses — a defect that appears to be driven by hyperglycemia. Despite these novel observations, the relationship between hyperglycemia and impaired anti-inflammatory responses (and the underlying mechanisms) across individuals with varying levels of glycemic control has not been examined. Moreover, the ability of a lifestyle intervention to restore anti-inflammatory responses via normalization of blood glucose levels in individuals with T2D has not been evaluated. As such, we aim to: 1) determine whether a dose-response relationship exists between the level of hyperglycemia and magnitude of impairment in anti-inflammatory responses across individuals with varying levels of glycemic control, 2) explore the mechanisms linking hyperglycemia to impaired anti-inflammatory responses, and 3) evaluate the efficacy of a daily post-meal walking intervention to restore anti-inflammatory responses in individuals with T2D.

Even in the absence of disease, ageing leads to impairments in muscle function, limiting the abilities of many older adults to perform daily activities, such as walking. These functional declines are due to ageing-related impairments in the brain, spinal cord, and muscles. However, these declines in function are poorly understood in adults over 80 years of age, which is especially true for older females, as these groups are typically omitted from human physiology research.

To improve our understanding of ageing-related changes in muscle function, we will evaluate brain, spinal cord, and muscle function during force or power production and compare differences among young (18-30 years), old (60-69 years), and very old (over 80 years) females and males. The inclusion of very old adults is critical, as these individuals are most susceptible to impairments in muscle function. Furthermore, we are focusing our efforts on the thigh muscles, as they are vital for daily activities and mobility, and are greatly impacted by advancing age. This project will provide foundational knowledge to guide the development of interventions, such as age- and sex-specific exercise prescriptions, to restore muscle function and quality of life for older adults.

Multiple sclerosis (MS) likely begins years before the first neurological symptom by a set of not-clearly defined, subtle symptoms, leading patients to increasingly seek medical attention years before diagnosis. Some may even require psychiatric care during this period. This phase of the disease is known as the MS prodrome. Our plan is to better characterize psychiatric healthcare encounters during this phase of the disease by analyzing anonymized and linked administrative health data that is generated whenever an individual visits a doctor, is admitted to a hospital, or fills a prescription at a pharmacy. We aim to specifically look at any visits resulting in a diagnosis of depression, anxiety, or bipolar disorder by a physician, any visits to psychiatrists, and also look at prescriptions filled for medications, such as antidepressants. These ‘psychiatric data’ generated during the five years before patients’ first MS symptom will be explored and compared to that of individuals from the general population. We believe that advancing our understanding of the MS prodrome may help us identify patients sooner in their disease course, allowing for earlier treatment, and eventually prevent disease progression.