Neurodevelopmental and fertility disorders represent significant health burdens in Canada, as approximately 1 in 66 Canadian youth are diagnosed with an autism spectrum disorder, and 1 in 6 Canadian couples experience infertility. Neurons and reproductive cells (oocytes and sperm) rely extensively on a form of control of gene expression called translational control. Mutations in the translational regulatory gene Fmr1 underlie the fragile X disorders known as fragile X syndrome (FXS) and fragile X primary ovarian insufficiency (FXPOI), which are leading causes of autism and premature ovarian failure respectively.
The proposed research will build upon my recent discoveries of Fmr1’s role in promoting the translation of genes encoding large proteins — many of which are associated with autism — in order to understand the mechanism by which Fmr1 activates translation. Knowledge of this mechanism will be of immense clinical value, enabling the development of novel therapies for citizens of British Columbia experiencing a fragile X disorder or related autism spectrum or infertility disorder.
In Canada, approximately 7,600 adolescents and young adults (AYAs) aged 15 to 39 are diagnosed with cancer each year, representing 4 percent of annual cancer diagnoses. Currently, cancer care systems have limited capacity to meet the complex needs of AYAs and survival outcomes for AYAs are often worse when compared to children and adults over 40.
This research program will use the principles of participatory action research (PAR) and patient-oriented research (POR) to meaningfully engage AYAs and cancer care allies (healthcare professionals, decision makers, researchers, and community organizations) to better understand AYA cancer care and explore how cancer care systems can respond to the unique, complex needs of AYAs with cancer. Led by a researcher with lived experience of cancer as an AYA and 15 years of experience conducting PAR, the work seeks to inform AYA cancer care research, policy, and practice in BC and beyond. Initial research funding from the Vancouver Foundation, MSFHR, and British Academy is in place, as are collaborators from Royal Roads University, BC Cancer, BC Ministry of Health, Young Adult Cancer Canada, the BC SUPPORT Unit, Callanish Society, InspireHealth, Innovation Support Unit, and AYAs with cancer.
Obesity is one of many chronic conditions that are rising in Canada, with heart disease as the top killer for women. Social inequalities exist in these conditions, but few studies focus on the social causes of obesity in women versus men, or on how social causes reinforce each other.
My research program aims to fill these knowledge gaps so that interventions to prevent and manage chronic conditions can be better designed and more effective. One of my projects is focused on co-developing novel ways to promote heart health among Indigenous women because of the profound burden of CVD in one of Canada’s most marginalised group. A key program goal is to produce strong research evidence to inform public health strategies and interventions for preventive action on obesity, and to build capacity of the next generation of researchers and healthcare providers to further improve health and health equity in Canada, especially BC.
In many resource-limited countries, children who suffer from severe illness are at a high risk of dying in the six months after leaving the hospital. Most caregivers are unaware of this, although simple strategies like follow-up visits and healthy practices at home can improve survival. Our team has developed a tool that allows healthcare workers to identify children who are most at risk of dying after leaving the hospital. Healthcare workers can use this tool to identify the highest-risk children and plan follow-up visits, reducing the burden on families and the health system. The caregivers of all discharged children receive education on healthy practices and on the signs that their child needs follow-up care. In Uganda, our approach has saved the lives of children aged six months to five years old.
Here, we will confirm that this same approach can be used in a wider population. We will talk to families and healthcare workers to determine how best use this approach in different age groups and locations. We will work closely with our Ugandan partners to ensure improvements are long-lasting. Ultimately, we plan to work with our local partners to apply our approach and improve child health in remote communities across BC.
T cells patrol the body using their T cell receptors (TCR) to look for cells which display evidence of intracellular pathogens or cancers. In order to focus their attention on specific cancer antigens, T cells can be engineered to express an artificial recognition receptor (termed a Chimeric Antigen Receptor or CAR). CAR technology has been shown to be extremely powerful clinically in leukaemia and lymphoma patients who have not responded to other lines of therapy, leading to recent FDA and Health Canada approvals.
However, only one third of lymphoma patients treated with CD19 specific CAR T cells exhibit long lasting curative responses, thus leaving significant room for improvement. CAR T failure can usually be attributed to either loss of the tumour antigen (ie CD19) or to dysfunction of the T cells, and we are developing a strategy to address the latter. Once T cells express a CAR, they can still receive signals through their TCR, and we have shown in preliminary experiments that this type of stimulation can help CAR T cells to proliferate and kill tumour cells. Our research will use oncolytic cancer killing viruses, and other vaccines, to help mobilize CAR T cells which recognize viral antigens using their TCR.
Every week, at least 500,000 Canadian employees are unable to work due to poor mental health, costing employers upwards of $6 billion in lost productivity. In healthcare, poor employee mental health leads to patient suffering and death and severe rates of staff absenteeism and turnover. Nurses, who constitute the largest human resource in healthcare, experience a disproportionately high rate of depression and posttraumatic stress disorder, and these conditions severely impact patient outcomes. COVID-19 has exacerbated the already numerous workplace risk factors that nurses face, with especially damaging impacts in the long-term care sector (LTC).
COVID-19 has had a devastating impact on workplace psychological health and safety for nurses across healthcare contexts, and especially in LTC. My research responds to this urgent need to improve the quality and safety of resident care provision by improving the workplace conditions for nurses in LTC, driving better systems and patient outcomes. I will work with new and existing partners to identify, implement, and evaluate best practices and policies in this sector. This research will have vast implications for scholarship, policy, and the success of healthcare ecosystems in Canada.
Antibody therapies have revolutionized modern medicine: they offer highly specific and effective treatments, with applications in oncology and rare diseases. The drawback of current antibody therapies is that they are expensive and must be administered intravenously, which limits widespread use. RNA-based gene therapy is a potential way to encode antibodies to make these treatments more universally affordable and accessible. For example, RNA-based gene therapy is used in the leading COVID-19 vaccines because it is easy to produce rapidly and cost-effectively at large scales. While RNA vaccines or protein replacement therapies have been widely investigated, the application to RNA-encoded antibodies is still in the early development phase. The main challenge is delivering sufficient amounts of RNA to target cells and ensuring the duration of antibody expression is therapeutically relevant. We aim to use self-amplifying RNA (saRNA), a type of RNA that replicates itself in cells, to encode antibodies. saRNA results in higher protein expression than normal RNA using a lower dose of RNA. We hypothesize that by optimizing the formulation saRNA will enable a low-cost, easily administered approach to antibody therapy.
Stem cells offer tremendous potential for tissue regeneration and uncovering causes and treatments for many human diseases. Technologies developed over the past decade now allow us to grow human stem cells in the lab and manipulate them to carry disease-causing gene mutations and turn them into any cell type of interest. My lab’s research uses these powerful tools to identify important regulators of stem cell function, particularly as they develop into cell types relevant to brain disorders. We focus on identifying the biological processes that build our brains, and biomarkers and treatment approaches for diseases.
Though the genes that regulate stem cell function are fairly well know, the impact of cell organelles, which coordinate many biological functions and are potential targets for treatment, is poorly understood. My lab is working to bridge this gap by investigating the impact of vesicle-like organelles called lysosomes on brain stem cells. Our data suggests lysosomes are critical regulators of stem cell function and brain development. Given new imaging-based tools and clinically approved lysosome-targeted drugs, studying the role of lysosomes can transform our potential to understand, diagnose, and treat brain disease.
Although researchers have identified tens of thousands of disease-associated genetic variants, the mechanisms driving most of these variants remains unknown. Most variants are believed to affect regulatory elements. However, regulatory elements are incompletely annotated and understood. Large-scale projects have recently generated thousands of epigenomic data sets. These data sets measure the regulatory activity of the genome in human cells. However, computational methods are needed to understand the link between genetic variation and disease.
We previously developed a computational method, Segway, that annotates genomic regulatory elements on the basis of epigenomic data sets. Enabled by new epigenetic data sets, this project will annotate the genome in hundreds of human cell types, and use these annotations to understand disease-associated genetic variation.
Additionally, we will develop computational methods that improve our ability to identify genomic elements. This outputs of this project will come in three forms:
- General-purpose software for annotating the genome.
- Easy-to-use reference data sets.
- Insights into the link between genetic variation and chronic obstructive pulmonary disease (COPD).
Neurodevelopmental disorders (NDDs) impact 7 to 14 percent of all children in developed countries. NDDs are incredibility heterogeneous and are caused by a complex interaction of genetic and environmental risk factors. One of the most consistent findings across NDDs is altered immune function, but it is unclear if neuroinflammation is a cause or consequence of brain pathology. My laboratory will directly test for causality and identify the optimal mechanisms and timepoints for immune based interventions in NDDs. Targets and compounds that impact microglia, the main immune cell in the brain, have immense potential for treating a broad range of NDDs.
