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.
Program: Trainee
Developing the next generation of therapeutic regulatory T cells using CRISPR/Cas9
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.
Physical exercise to mitigate the effects of physical inactivity on brain health
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.
Anti-inflammatory cytokine function in individuals with type 2 diabetes: Impact of hyperglycemia and the restorative effects of exercise
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.
Neural and muscular mechanisms of age- and sex-related impairments in muscle function and fatigue in old and very old adults
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.
Psychiatric morbidity in multiple sclerosis during the prodromal period (Psych-MS)
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.
Using a mobile health aerobic exercise program to improve psychological distress in healthcare professionals: A randomised controlled trial
Healthcare professionals account for the largest sector of government employees in Canada and report more than twice as much high work stress and greater depression than the average employed Canadian. Due to the current pandemic, healthcare professionals are now reporting an increase in their depression, anxiety, and distress linked to their risk of becoming infected with COVID-19, quarantine and isolation, and being separated from their families. The stress faced by healthcare professionals should be cause for concern among our public health organizations, as stress has serious health consequences for healthcare workers, including medical errors, depression, burnout, absenteeism, and premature mortality. I am proposing to conduct a randomised trial of an aerobic exercise mobile app intervention (yoga and whole body weight-based training) that requires little physical space or equipment and is easily completed at home or in a small office, to improve healthcare professionals’ psychological distress and wellbeing. This work is expected to provide a feasible, engaging, and accessible solution to implement in every medical setting that will improve work stress, health, and quality of life among Canadian healthcare professionals.
Building on the strengths of first responders as a critical first point of contact: Improving emergency care in remote Indigenous communities
Applying an ethnographic and story-based approach, the objective of this project is to develop a deeper understanding of the unique challenges faced by first responders in four remote Indigenous communities on the West Coast of Vancouver Island. Working collaboratively with first responders and community health leaders, this project will identify: existing community supports; interventions that can improve the experiences and effectiveness of first responders; and an assessment of these interventions. First responders provide a critical first point of contact for serious injury or accidents in many remote Indigenous communities. These positions are often held by unpaid volunteers with little access to supports such as training and post-incident clinical debriefing. Despite these challenges, they provide an invaluable service to their communities, access to emergency services has been identified as contributing to the health disparities faced by Indigenous communities. Improving effectiveness of first responders in emergency situations will require building on the strengths already present within communities, by identifying avenues for more sustainable first response services and support.
Role of SASH1 in generation of hematopoietic stem cells
For many patients with a serious blood disorder or malignancy the primary treatment option is a stem cell transplant (SCT), which involves destroying the unhealthy blood cells of the patient and replacing them with healthy donor stem cells. Unfortunately, a large number of patients are unable to find a suitable donor, and die as a result. Thus, there is an urgent need to identify new sources of healthy blood stem cells for these patients.
One promising solution is to harvest other types of cells from the patient and reprogram them to become blood stem cells, which can then be reintroduced later. Key to the success of this approach is placing the cells in an environment which mimics how the first blood cells are generated during embryonic development (called endothelial to hematopoietic transition [EHT]). To date little research has focused on the external cues needed for EHT, and this presents a bottleneck to producing stem cells for SCT. Therefore, our project will use models of EHT to identify external drivers of EHT, and the mechanisms by which they program cells to transition into blood cells. The knowledge from this project will help to create protocols to reproducibly reprogram patient-derived cells into blood cells for SCT.
Multifunctional immunomodulating conjugates for targeting and treating glycocalyx dysfunction in inflammatory conditions
Diseases that involve the heart or blood vessels, autoimmune diseases (e.g. diabetes, multiple sclerosis), or the rejection of transplanted organs affect about 1 in 3 Canadians and constitute a significant cost to the Canadian economy. In the perpetuation of these diseases glycocalyx shedding plays a key role. The glycocalyx (literally meaning “sugar coat”) is a sugar polymer-based structure that covers the surface of the cells, which are lining all organs and blood vessels. It lies at the interface between bloodstream and organ tissue and represents the protective front line against inflammatory and immune-mediated diseases. Thus, we aim to specifically target and treat glycocalyx dysfunction by rapidly rebuilding it through a new cell surface engineering approach, which should enable organs to maintain or reestablish their function. To do so, we will develop polymer conjugates which can selectively bind and retain on the endothelial cell surface. The conjugates will present sugar moieties which resemble the natural glycocalyx layer. We anticipate to realize a novel approach with significant therapeutic potential to improve treatment for diverse disease conditions where glycocalyx dysfunction is contributing to the pathology.