Chronic motor impairments are experienced by 85% of stroke survivors. Recovery of these impairments can be facilitated by repetitive non-physical motor practice including kinaesthetic motor imagery (KMI; the mental rehearsal of movement), visual motor imagery (VMI; specific focus on a mental image) and action observation (AO; passive observation of movement). Yet, effectiveness of these different non-physical practice modes is varied due to highly individualized brain function after stroke. To improve effectiveness, we will assess brain and behaviour changes driven by KMI, VMI, and AO at the individual participant level. We will then design a personalized intervention to show that improvements in motor function are maximized when practice mode is tailored to the individual based on the brain’s response to each mode. This research informs the development of evidence-based interventions after stroke, representing an important step in improving the quality of life of stroke survivors in Canada. Integrated knowledge translation (KT) activities (including engaging key knowledge users), and end-study KT activities (including public lectures of findings) will be conducted.
Program: Trainee
Addressing antimicrobial resistance through the design and preclinical evaluation of a Klebsiella pneumoniae vaccine
Antibacterial resistance occurs when bacterial infections become resistant to treatment. It is a serious and growing threat to global health. Klebsiella pneumoniae (Kp) is a bacteria that causes a wide range of infections, particularly in vulnerable populations such as children and immunocompromised adults. Kp can develop multi-drug resistance, which makes finding treatments difficult and increases the risk of severe complications or death. Finding novel treatments for Kp infections is a priority for both the World Health Organization and the Canadian government. Our goal is to develop a vaccine against Kp, which would reduce the incidence of Kp infection for both treatable and untreatable cases, and limit the opportunities for this bacteria to develop even stronger resistance to treatments.
In this project, I will focus on developing a vaccine that targets drug-resistant Kp. First, I need to identify vaccine targets that are present in most drug-resistant Kp infections. Then, I will develop vaccines using those targets. In the next step I will test whether our different vaccines protect mice from lung, bloodstream, and urinary tract infections. With these data, we will move the best candidate vaccine forward to clinical trials.
Developing novel strategies to enhance CAR Treg manufacture and testing in transplantation
After organ transplantation, patients must take immunosuppressive drugs to prevent rejection of the organ by their immune system. However, these drugs have severe side-effects. In contrast, regulatory T cell (Treg) therapy, which uses naturally suppressive immune cells to produce immunosuppression, can avoid these side-effects. Tregs for therapy can be isolated from patients, genetically modified in the lab, and infused back into patients to block unwanted immune responses without broader effects. However, improvements are still needed to this therapy. This project takes two strategies to enhance Treg therapy. Firstly, I will test the effect of supplementing lactic acid during cell growth in order to identify an optimal media composition that promotes function. Secondly, I will develop a human organ-in-a-dish system to model complicated transplantation immune responses in a lab without using mouse models, which often don’t replicate events in humans. Overall, this work will produce Tregs that function and survive better when administered to patients and develop a new way to test and model Treg function in a complex human system.
Engineering Transfusable Platelets for Improved Hemorrhage Control
Failure to control bleeding, such as during trauma and childbirth, accounts for more than half of all operating room deaths. Platelets are blood cells that stick to sites of active bleeding and release proteins to initiate blood clotting. The gold standard therapy for treating severe bleeds is transfusing the patient with more platelets. However, in some cases, transfused platelets can have impaired clotting, thus increasing mortality. A strategy to improve platelet function is to load platelets with more clot-initiating proteins. We have previously shown that platelets can be engineered to express new proteins using mRNA-lipid nanoparticles (mRNA-LNP). This project will expand on these findings and use mRNA-LNP to deliver the genetic blueprint for clot-initiating proteins into platelets to enable the production of clotting factors that will prime the platelets for improved clotting. The research will be in active collaboration with academic and industrial partners to facilitate the development of a clinical product from any generated intellectual property. Enhancing the natural properties of platelets will improve options for bleeding control, with the potential to reduce the incidence of hemorrhage-related deaths in Canada.
Investigating oncogenic mechanisms in DICER1 syndrome-associated ovarian Sertoli-Leydig cell tumors
DICER1 syndrome is a rare, inherited disorder; individuals with a mutation (change) in the DICER1 gene are at increased risk of a variety of cancerous and non-cancerous (benign) tumors. It affects mostly children and young adults. These cancers can be lethal at advanced stages of disease with no biologically-informed treatment strategies available. Despite the discovery of the gene, DICER1, being attributed to cancer development, the translation of this genomic discovery to the bedside to improve cancer care has been hindered by the lack of relevant models to study the disease. My post-doctoral research project will focus on one such aggressive rare cancer, called ovarian Sertoli-Leydig cell tumor. I will use the unique tools/resources such as a large cohort of patient samples and the first-ever mouse model of DICER1 syndrome-associated cancer to understand the biology of this rare ovarian cancer and identify potential druggable candidates for future therapeutic development.
Risk factors for cognitive impairment and substance-induced psychosis in people living in precarious housing or homelessness.
Social marginalization is a risk factor for poor health and is associated with psychotic and substance use disorders, traumatic brain injury (TBI), HIV and hepatitis C infection. Substance use and brain insults, such as TBIs, can lead to changes in brain function, yet we do not fully understand how they contribute to cognitive impairment (possibly due to accelerated aging) and other symptoms like psychosis. This study aims to assess the extent to which individuals with brain insults using substances are at risk of cognitive impairment or psychosis, and if using antipsychotics can affect these symptoms. This study will use data from the Hotel Study, an ongoing longitudinal community-based study aimed at characterizing factors affecting health of marginalized individuals based in Vancouver’s Downtown Eastside. Participants completed comprehensive assessments at study entry and monthly evaluations of prescription and non-prescription substance use, symptoms of psychosis, and annual cognitive assessments including brain imaging. Statistical modelling will be used to address objectives. We anticipate that our results will help better guide clinicians in engaging and treating this vulnerable population to prevent chronic disability.
Gender equity through strengthening maternal nutrition and health in resource-limited settings
Rural, remote and marginalized people in areas of suboptimal healthcare service delivery are at increased risk of poor health outcomes during and after pregnancy, such as high blood pressure. Eating nutritious foods during pregnancy has been recognized to support healthy development of the baby, but less is known about the impact on the health of mothers, especially after childbirth. This gap limits the ability to make evidence-based recommendations and contributes to a lower prioritization of mothers’ well-being.
The proposed research seeks to answer the following research questions:
1. What is the current evidence on the impact of nutrition on women’s health during and after pregnancy?
2. Is there a relationship between maternal diets with imbalanced nutrients in sub-Saharan African countries and developing high blood pressure between 20-34 weeks of pregnancy, after 34 weeks, and/or after childbirth?
3. What strategies can be co-designed with community partners to strengthen maternal nutrition and health capacities of vulnerable pregnant populations?
Findings aim to support maternal interventions to support gender equity and reduce health inequities for rural, remote and marginalized populations in Canada and globally.
Use of CAR Tregs to induce transplantation tolerance
Organ transplantation, the primary treatment for organ failure, necessitates lifelong immunosuppressive therapy. Traditional immunosuppressants like steroids pose risks of severe infections and cancer due to their non-specific action. To address this, we’ve developed engineered Tregs, which migrate specifically to transplanted organs and prevent rejection. Initial studies in mice demonstrate promising delay in skin graft rejection. However, the effectiveness of Tregs combined with various immunosuppressive drugs used in transplantation remains unclear. My research aims to bridge this gap by investigating how engineered Tregs interact with common drugs to identify optimal combination therapies for transplant tolerance induction. I will also explore the underlying mechanisms of immune suppression. Ultimately, this work will inform the design of clinical trials, optimizing drug-Treg combinations as a therapeutic approach to combat transplant rejection.
AI-based Platform for Ovarian Cancer Biomarker Discovery and Refinement
Ovarian cancer ranks fifth in cancer deaths among women. The revolution in our understanding of genetic and molecular drivers of other cancers has resulted in major improvements in how such cancers are routinely managed. However, standard clinical management of ovarian cancer have not seen any improvements. Significant clinical implications have been achieved by the classification of ovarian cancer based on genetic markers. Pathologists achieve a cornerstone in cancer diagnosis and prognostication by studying the visual microscopic study of diseased tissue (histology). Histology reveals wealth visual information of disease biology about the aggregation effect of genetic alterations on cancer cells. In this project, we plan to produce automated AI-based differential diagnostic tool for major ovarian cancer subtypes, and moreover, investigate the relationship between genetic markers, histology and disease outcome. We then combine these kinds of data for a comprehensive profile of each tumor. New knowledge generated from this project will shed light on the link between histology and genetic markers and identify potential biomarkers that can be rapidly and accurately tested to stratify ovarian cancer for accurate treatment selection.
Using unbiased whole brain methods to understand how impact direction affects the neuropathology of traumatic brain injury in mice
Traumatic Brain Injury (TBI) is a leading cause of death and disability worldwide and often caused by falls, motor vehicle accidents, sports, and violence. Most TBIs are mild (concussion-like) and involve head motion in one or more planes. Although many clinical studies show that complex rotational head motion is associated with worse outcomes, the underlying reasons are unknown. My project aims to fill this gap by determining how head motion during impact relates to changes in levels of injury blood biomarkers and brain pathology in mice. Using our established non-surgical TBI model called CHIMERA (to imitate human TBI), I will deliver impact to the back or side of the head, and measure how the head moves during these impacts using high-speed cameras. I will use cutting edge tissue clearing method to examine brain in 3D and map changes in neuronal activity, axonal and vascular integrity. I will test how these impacts lead to changes in blood biomarkers using clinically relevant tests. Overall, this study will help us understand how impact biomechanics relates to TBI outcomes, which is tremendously important for the future design of helmets and other safety equipment, sport coaching, and concussion rehabilitation.