Cells that are the building blocks of the organism come in different forms and functions. Stem cells are a unique type of cells, because of their ability to change (differentiate) or maintain their state. Because of this ability to differentiate into any type of cell, stem cells are on the frontiers of regenerative medicine, which is aimed to restore damaged cells, tissues or organs. The cell division (mitosis) poses a challenge for cell identity. During mitosis, the DNA is condensed into characteristic mitotic chromosomes, the nuclear membrane, separating DNA from rest of the cell, is fragmented, and the gene expression ceases. How then cells memorized which genes were expressed, to continue their expression after mitosis? The mitotic memory has been proposed as a mechanism for the maintenance of cell identity after mitosis. One arm of this mechanism, called bookmarking, is the binding of transcription factors (proteins regulating gene expression), to mitotic DNA. This project aims to establish the molecular mechanisms of mitotic bookmarking in mouse embryonic stem cells. Using methods, such as gene editing, genomics, and imaging, I will solve how stem cells maintain their identity after countless number of cell division.
Program: Trainee
The impact of olfactory dysfunction on social and mental health
Our sense of smell enriches our lives—from enhancing pleasures (e.g. aroma of coffee) to signalling danger (e.g. smoke). Loss of smell is related to a range of social and emotional impairments, including elevated rates of depression, social isolation, and relationship difficulties. The COVID-19 pandemic causes transient smell loss, providing a novel opportunity to study one of our least understood senses. My first aim is to examine pathways linking olfactory loss to social and emotional impairments. I will recruit a prospective cohort of adults with recent onset of olfactory dysfunction and no flu-like symptoms (N=300) as well as a control cohort (N=100). Participants will be assessed over eight weeks, covering the typical period for olfactory recovery in COVID-19 patients. This data will provide a first-ever look at how within-person changes in olfaction relate to changes in social and emotional wellbeing. My second aim is to develop a brief, behavioral intervention by conducting a randomized trial focused on the benefit to participants from an online intervention. After refinement, this intervention will be offered freely, and findings will inform efforts to improve mental health for people with olfactory dysfunctions.
Determination of the optimal SARS-CoV-2 vaccination strategy to achieve a robust and long-lasting immune response
Global COVID-19 vaccine distribution has been inequitable, with high-income countries afforded widespread access to vaccines and boosters, while among the low-income countries only 2 percent of individuals are vaccinated. Consequently, over 50 percent of the world’s population remains unvaccinated. Fortunately, however, data from vaccinated cohorts can inform the most efficient and effective community-level vaccination strategies for the unvaccinated populations. Currently approved mRNA vaccines were initially tested with dosing intervals of 21-28 days; however, this may lead to suboptimal immunity. Further, data informing the optimal timing and frequency of booster doses is lacking. This project will answer critical questions regarding the optimal vaccination strategies to achieve a robust long-lasting immune response. In this study I will employ data from a prospective national cohort of adult paramedics, providing sociodemographic data and serum blood samples. I will identify the optimal vaccination strategies to achieving a robust immune response at 12, 18 and 24 months, including examining differences between sex, race, and age. These data will inform ongoing global vaccination efforts, to maximize efficiency and long-term protection.
Impact of a combined exercise and counselling intervention on mental health in people with spinal cord injury who live with chronic pain: A psychobiological approach
People with spinal cord injury (SCI) who live with chronic pain report poorer mental health (e.g. depression and anxiety symptoms) than those without disability. Poor mental health can further limit social participation (including employment) and physical functioning, and increase the use of health care services. Therefore, there is a need for safe, accessible, and affordable strategies to improve pain and mental health in this population. Exercise may be an effective strategy, but it’s not known if people with SCI living with chronic pain also benefit. Forty-two adults with SCI reporting chronic pain will receive a personalized exercise prescription and weekly exercise counselling. An equal group will go on a waitlist. After six months, we will test for differences in mental health between the groups, and if changes in fitness, pain or social factors can explain these differences. We will interview participants to gather their perspectives on the program, and what we can do better to improve mental health. This study will be the first to test if exercising improves mental health, how much exercise is needed, and the processes by which exercise may improve mental health in people living with SCI and chronic pain.
The role of Baf53b in regulating neuronal gene expression and autism behaviours across development
Autism spectrum disorder (ASD) is characterized by impairments in social communication and restricted interests. Several genes have been implicated in ASD, but a group of genes in the neuronal nBAF complex have emerged as promising candidates. The nBAF complex changes the structure of DNA to influence the way several genes are expressed in a cell. To date, no research has been conducted on the role of nBAF within neuron subtypes. I will investigate the loss of the nBAF complex specifically in parvalbumin (PV) neurons in mice. PV neurons are the most abundant type of inhibitory neuron in the brain and are frequently impaired in ASD. I hypothesize that loss of the nBAF complex will alter gene expression that is necessary for proper neuron function and resulting in ASD-like behaviours. Mice lacking the nBAF complex will undergo behavioural tests that can be used as a proxy to study ASD. Next generation sequencing will be employed to investigate alterations in gene expression. This work will be the first to test how loss of the nBAF complex specifically in PV neurons might lead to behavioural changes relevant to ASDs, providing the foundation for potential treatments.
Improving access to breastfeeding support in British Columbia: Needs assessment of a virtual health intervention
Breastfeeding has numerous benefits for parents and infants. However, many parents encounter challenges with breastfeeding that can lead to early breastfeeding cessation. In addition, persons across British Columbia (BC), especially those in rural or remote regions, cannot access breastfeeding support. This has been especially true during the COVID-19 pandemic, as social distancing protocols and anxiety over personal safety have decreased opportunities for face-to-face interactions. My postdoctoral work will identify effective telehealth strategies and interventions to deliver breastfeeding support to persons living in BC. This study will have three phases: a literature review of effective virtual breastfeeding support; interviews to understand the support needs and acceptance of virtual breastfeeding support among healthcare providers and persons; and development of a clinical guideline for virtual breastfeeding support. Knowledge gained from this study will be used to develop a framework for the provision of virtual breastfeeding support. In addition, it will inform health policy, research, and practice for new parents living in rural BC or those who experience challenges in receiving face-to-face breastfeeding support.
Proteome-wide mechanisms of hyperinsulinemia and sucrose-induced, tissue-specific insulin resistance
During the development of Type 2 diabetes, the body often makes more of the blood sugar-lowering hormone insulin than normal. Recent research suggests excess insulin may cause weight gain and insensitivity to insulin. Studies from our lab showed that preventing this increase of insulin can reduce weight gain and extends lifespan in mice. Too much sugar consumption also contributes to obesity and diabetes, but how this happens is still unclear. Therefore, we aim to find out whether reducing insulin can prevent the detrimental effects of high sucrose and identify the underlying causes of obesity and diabetes. So far, our experiments with mice who were given sucrose drink in place of water, have revealed that mice given that have been genetically modified to produce less insulin are protected from higher body weight and blood sugar levels. With funding from Health Research BC, we will analyze the liver, muscle, and fat of these mice using powerful techniques that can profile thousands of genes and proteins in these tissues, rather than just a few at a time. These analyses will reveal the detailed changes in the cells in response to sucrose and insulin, which will tell us how they cause obesity and diabetes and help us develop strategies for preventing diabetes.
Exploration through movement variability: How does the presence of pain affect the movement variability-adaptation process of walking?
When we walk, our bodies take each step slightly differently. This variability is how the brain explores movements so we can adapt to changing environments (e.g. bump in the sidewalk) or new challenges (e.g. painful motion). Pain from injuries or disease can lower this natural exploration because our brain avoids painful movements, ultimately limiting our ability to adapt. My study aims to understand how pain affects this variability-adaptation process in walking. In these studies, we will use electrical stimulation to create artificial knee pain, since naturally occurring pain fluctuates and is difficult to control. By synchronizing the painful stimulation with walking motions, we can precisely control the timing and severity of pain so we can measure the variability-adaptation process in real-time. First, we will test how knee pain changes movement variability. Then, we will measure how adaptation is affected by lower variability created by the pain. To conduct these projects, we will develop new wearable technology that combines electrical stimulation and motion tracking devices to perform this work in places outside the lab. The results will inform how movement variability can affect rehabilitation of painful conditions.
A novel stem cell model for human islet development and cytoarchitecture
The cultivation of stem cells to insulin-producing beta cells offers an unlimited source of transplantable material for diabetes treatment. However, currently manufactured beta cells do not function precisely like the healthy ones in our bodies. Human islets are cell clusters mainly comprised of a mix of endocrine cell types, and interactions among them are critical in controlling insulin secretion. However, this point has been overlooked by current manufacturing methods that typically attempt to make clusters enriched only for beta cells. The absence of other islet cell types may therefore be a leading cause of the failure to obtain properly regulated insulin production. We recently developed a method to coax stem cells into islet clusters that are enriched for major endocrine cell types. Interestingly, these islets formed through an essential but unidentified “budding process” and self-organized into distinct cellular arrangements over time. Our goal is to elucidate the mechanisms that regulate islet formation, including the ways in which the cells assemble and impact islet function. Success could facilitate methods to manufacture islet cells with more robust insulin production and guide cell replacement strategies for diabetes.
The role of Inflammatory bowel disease in the development of Alzheimer’s disease
People with inflammatory bowel disease (IBD) are six times as likely to develop Alzheimer’s disease and on average seven years sooner than people without IBD. IBD will affect 1 percent of Canadians in the next 10 years and there is no cure for this illness. IBD causes intestinal microbiome, neural, immune, and endocrine dysregulation, but the exact mechanisms that drive the development of Alzheimer’s and other dementias are unknown.
The goal of my research is to elucidate the mechanisms by which IBD increases the risk of Alzheimer’s and dementia with the long-term goal of developing pharmacological interventions.