Stroke is a leading cause of long-term disability in Canada that causes movement impairments on one side of the body. In cases of severe movement impairment, there is often extensive damage to the primary descending motor pathway in the brain originating from the opposite side of the body. When this pathway is damaged, secondary motor pathways are altered which may support recovery in these individuals. Several of these secondary motor pathways originate from the same side of the brain as the impaired limb and are therefore undamaged in cases of stroke. My research aims to comprehensively investigate the role of the secondary motor pathways in motor function with chronic stroke survivors that have severe movement impairments. This research will use a combination of state-of-the-art brain stimulation and brain imaging techniques to gain novel insight into the relationship between the secondary motor pathways and the control of voluntary movement. My research will provide valuable insight into the role of the alternative motor pathways. In turn this information can be used in clinical practice to implement rehabilitation strategies that lead to better recovery and improved quality of life in individuals with severe strokes.
Program: Trainee
Engagement in opioid agonist therapy and risk for repeat overdose in people living with and without HIV who experienced a nonfatal opioid overdose: Providing insight to improve clinical care
The ongoing drug toxicity and overdose (OD) crisis has ruined the lives of many people in British Columbia (BC). Opioid agonist therapy (OAT) reduces the risk for an OD, but not everyone who needs OAT has access to and is taking OAT. People living with HIV (PLWH) are disproportionately affected by the OD crisis and may be less likely to have access to OAT. This project aims to contribute to a strategy to connect people who visit an emergency department (ED) or a hospital due to a nonfatal opioid OD (NFOOD) with primary care and OAT. I will use routinely collected health data on all PLWH and a 10 percent random sample of the general population in BC, between 1992 and 2020. I will investigate — of everyone who visited an ED or a hospital after a NFOOD — who is most at risk of 1) not being connected to primary care and OAT, and 2) a repeated OD. I will compare people living with and without HIV. I also will have conversations with professionals from various backgrounds and individuals with lived and living experience. Through these, I hope to learn more about barriers to care. Based on what I learned, I will formulate recommendations on how to help people that experienced a NFOOD connect with care that best suits their needs, including OAT.
Pain and healthcare experiences of sex and gender minority citizens living with chronic pain in Canada
One in four people in Canada live with chronic pain. These individuals experience poorer health outcomes, higher healthcare services use, and lower quality of life. Studies show males and females experience pain differently, for example differences in pain sensitivity and pain control. But little is known about pain experiences in people who identify as a sex and gender minority, meaning a person’s sexual orientation or gender identity differs from traditional societal views. Sex and gender minority persons report higher pain and experience unique life stressors (e.g. discrimination), which may lead to worsening of their pain. We aim to study 1) pain experiences and 2) strategies to improve healthcare experiences for individuals who identify as sex and gender minority living with chronic pain by collaborating with patient and public stakeholders to answer these questions. Involving persons who identify as sex and gender minority with chronic pain in research studies is important because it provides them with a voice to offer personal stories and perspectives. Community engagement will help researchers ask the “right questions” and guide research priorities to improve the lives of people who face similar health challenges.
The association of genetic risk factors with morphology and outcomes in interstitial lung disease
Interstitial lung disease (ILD) is a diverse group of illnesses with a variety of causes. The current approach to diagnosing ILD depends on the specific patterns observed on imaging studies (CT scan) and lung biopsy. There is increasing evidence that an individual’s genetics play a complex and important role in determining disease behaviour across different ILD subtypes. This study will examine whether common genetic risk factors predispose patients to different forms of ILD, influence treatment response, and predict prognosis. Investigating these genetic risk factors will improve our understanding of the biology that drives ILD and will help to develop a better system for ILD classification and diagnosis.
Fibrinogen promotes a microglial-mediated inflammatory response following adolescent repetitive mild traumatic brain injury
Concussions are a major health issue in Canada. Adolescents are an at-risk population for concussions because they are in an age range that is often engaged in contact sports and high-risk activities. Microglia, the brain’s resident immune cells, respond to these injuries, causing an inflammatory response. Concussions can damage brain blood vessels, promoting the release of fibrinogen, a protein not present in the healthy brain. Fibrinogen interacts with microglia, promoting an inflammatory profile that can alter neuronal functioning, leading to behavioural deficits. This project will block fibrinogen’s interaction with microglia using an ecologically valid rodent model of concussion. We will assess short- and long-term memory with well-known behavioural tests. In addition, we will assess microglial activation and type using immunohistochemistry, and assessing neuronal connectivity using field electrophysiology. Adolescence is a period of significant development marked by rapid learning and substantial brain growth/maturation. As such, expanding and fully characterizing changes in brain circuitry mediated by fibrinogen/microglia interactions following concussion may provide avenues for preventative and therapeutic interventions.
Cryo-EM studies of activators and inhibitors of KCNQ1 and KCNQ1:KCNE1 channel complexes
Type 1 Long QT syndrome (LQT1) and Short QT syndrome (SQT) result in life-threatening irregular heartbeats that can cause sudden death. LQT1 affects around 1 in 2,500 adults, whereas SQT may impact twice as many individuals, with high prevalence of congenital LQT in a First Nations community in Northern BC. Current treatments are inefficient and therefore, new therapeutic strategies are needed. Abnormalities of the protein, KCNQ1, result in these diseases. Normal KCNQ1 function moves charged ions through heart membranes. We generally know how KCNQ1 functions in health and disease; however, the exact mechanisms are not yet fully understood. We need to study the 3D structural changes that happen to KCNQ1 in the presence of certain compounds to understand how KCNQ1 functions. I will study the 3D structures of such complexes by using cryo-electron microscopy, a technique to study structural biology, and functional characterization. The new knowledge that will be produced will help better understand how such proteins cause disease and lead to new therapeutics for better human health.
Cholesteryl ester transfer protein-mediated regulation of HDL cholesterol levels and clinical outcomes in sepsis
Sepsis is the overwhelming immune system response that occurs when someone develops a serious infection, and is responsible for one-fifth of all deaths worldwide. Sepsis occurs when the immune system becomes over-activated by lipid components present in bacteria, and ultimately leads to dysfunction of critical organs and death. These bacterial lipids (called pathogen-associated lipids or ‘PALs’) are transported through the bloodstream by lipoproteins, the same “vehicles” that are used for cholesterol transport. Among these vehicles, high density lipoprotein (HDL) plays a central role transporting PALs. However, HDL levels significantly decrease during sepsis, leading to reduced clearance of PALs. In our previous work, we discovered that inhibiting a specific gene called cholesteryl ester transfer protein or CETP preserved HDL levels during sepsis, suggesting that this may be a new approach to treat sepsis. We now aim to study the mechanism by which CETP regulates HDL to combat bacteria, and whether CETP inhibition will improve mouse survival in a clinically-relevant sepsis model. Completion of this project will provide new insights into the therapeutic role of CETP inhibitor in sepsis, ultimately improving the health of Canadians.
Predictive biomarkers for ovarian cancer treatment: Analysis of patient of derived xenografts under treatment at single cell resolution
Each year in Canada, around 3,000 women will be diagnosed with high grade serous ovarian cancer (HGSOC) — the most common type of ovarian cancer. Despite good responses to first line treatments for many women, it comes back as a resistant disease. Targeted treatments such as PARP inhibitors (PARPi) have made a big difference to HGSOC that is deficient in a DNA repair pathway (Homologous recombination repair), but this only benefits around 50 percent of women with HGSOC. PARPi combinations with drugs that target angiogenesis and the immune response remain under investigation. This project will investigate how chemotherapy vs. targeted therapies differentially affects the DNA damage and immune response in cancer and how effective non-chemotherapy combination treatments work, including different doses and schedules. Also, which patient might benefit from which treatment and when for example should the targeted therapies be given before or after the chemotherapy? Creating models similar to humans, we will transplant patient tumors (removed at surgery) on the skin and inside the abdomen of mice and analyze the molecular nature (at single cell level) of these tumors before/after treatment. Results of these studies will inform future clinical trials.
Air pollution as a modulator of molecular, structural, and clinical outcomes in patients with fibrotic interstitial lung disease
Interstitial lung diseases (ILDs) are serious conditions resulting in lung scarring, breathing difficulties, and a severely shortened lifespan. Air pollution is associated with ILD development and progression, but we do not understand why. This project aims to answer this question by looking at cellular and genetic changes that occur in the lungs of patients with ILD following exposure to air pollution. Using satellite-derived air pollution and clinical data from patients, we will determine if certain genes result in worse clinical outcomes when patients with ILD are exposed to more air pollution. Next, we will examine how air pollution modifies how genes are turned on or off in ILDs, through a process called DNA methylation. Lastly, we will use high-resolution imaging tools to understand how the structure of the lungs change in response to air pollution in patients with ILD. This research will help us to understand how air pollution contributes to progressive lung scarring in patients with ILD and may identify new targets for therapies to reverse lung scarring. This work will inform environmental health policies aimed at protecting vulnerable populations, including patients with ILD and other chronic lung diseases.
Medulloblastoma plasma membrane proteomics to inform optimal immunotherapy design
Brain cancer is the most common pediatric solid cancer, devastating the lives of more than 5,000 children and their families every year in North America. Current chemoradiotherapy approaches are often ineffective and cause serious side effects on the developing brain, such as permanent seizures and learning disabilities. Thus, more effective and less damaging therapies are urgently needed. Immunotherapy has been recently credentialed as a breakthrough in cancer therapy, with novel immunotherapy agents approved by the FDA for the treatment of childhood cancer. There is every indication that this progress presents the tip of the iceberg and that with continued efforts, effective immunotherapies can be developed for many currently incurable pediatric cancers. The ability for cancers to grow rapidly is in part due to the activation of specific proteins exposed on the membrane of cancer cells. The goal of immunotherapy is to target cells exposing these proteins while sparing normal, healthy cells; however, a major barrier is that most proteins on the surface of medulloblastoma cells are currently unknown. In this proposal we will identify optimal targets to ultimately develop immunotherapies against medulloblastoma.