Cognitive decline is associated with a variety of neurodegenerative disorders and is increasingly prevalent in Canada’s aging population. One of the most effective means to counteract cognitive decline is to maintain or enhance cognitive reserve. Lifestyle factors have been shown to impact cognitive reserve, but this impact varies highly across individuals. Most investigations into the effects of lifestyle factors on behavior and neural function do not capture this inter-individual variability and produced mixed, difficult to reproduce findings. This research aims to reduce this variability by clustering the population into sub-types based on their susceptibility to lifestyle changes before investigating the causal relationships between lifestyle factors, behaviour and neural function. The identified causal relationships will serve as promising targets for future clinical interventions in sub-types of our aging population that can limit the effects of cognitive decline and lower the rates of neurodegenerative diseases. In addition to the classical means of knowledge translation, this research will be shared through public presentations held by the Institute of Neuroscience and Neurotechnology at Simon Fraser University.
Research Pillar: Biomedical Research
Structure-function relationship of retinal guanylyl cyclase, a key enzyme in phototransduction
Light adaptation is the ability of visual system to adjust its performance to the ambient level of illumination. It is fundamentally vital for the normal functioning of the visual system. During the normal cycle of day and night, the illumination of the earth’s surface varies over 11 orders of magnitude. The daily cycle of sensitivity adjustment is managed by switching between rod and cone pathways of retina. These pathways involve retinal guanylyl cyclase (retGC), an enzyme encoded by the GUCY2D gene expressed in rod and cone photoreceptors. In the light-induced signal cascade, retGC restores cGMP levels in the dark in a calcium-dependent manner. Mutations in GUCY2D are associated with recessive Leber congenital amaurosis-1 (LCA1) as well as dominant and recessive forms of cone-rod dystrophy (CORD). Presently, the molecular structure of retinal GC has not been determined; thus, its mechanism, interaction with other regulators, and identity of crucial residues conferring the activity of this enzyme have been elusive. We aim to fill this gap in our knowledge by determining the molecular structure of retGC. This information will enhance our understanding of the role of retGC in photoreceptors and diseases.
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.
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.
A personalized approach to non-physical practice after stroke
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.
Uncovering metabolic mechanisms for tumor-driven immunosuppression with mass spectrometry imaging
Scientists have uncovered ways to turn the body’s natural immune system against cancer – an approach termed immunotherapy. While highly effective for some patients and cancer types, many patients do not respond. This creates a fundamental knowledge gap: why do only certain patients respond to immunotherapies? The answer may lie in the adage – “you are what you eat”. Cancers, at the cellular level, consume lots of fats, sugars, and 1000’s of other molecules collectively termed ‘the metabolome’. This leads to immune cells needing to fight for key fuels, and tumor cell production of toxic by-products which can kill natural immune cells. Together, this can incapacitate the immune system and may be why immunotherapies fail. Resolving this metabolic hurdle will require emerging, state-of-the-art technologies that can distinguish cancer cell metabolism and immune cell metabolism as they exist in the tissue (i.e. with their spatial distribution preserved). This project aims to develop and apply cutting-edge technologies to profile tumors which are responsive & unresponsive to immunotherapy, providing a fundamental understanding of tumor metabolism and allowing us to identify new opportunities to improve targeted immunotherapy treatments.
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.
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.
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.
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.