Cost-efficient approach for phenotyping cells in large cohorts and relating them with COPD clinical outcomes

In Canada, over 2 million people suffer from COPD, costing over $1.5 billion per year in direct expenditures. However, no existing therapy can reverse COPD’s disease progress. Alveolar macrophages (AMs) are the lungs’ dominant immune cells and perform critical functions, including fighting infection and tissue repair. Single-cell genomics technology can characterize AM phenotypes and reveal their roles in COPD. However, validating the relation between AM phenotypes and COPD clinical outcomes requires many patients, making the unscalable single-cell technology impractical to study such large cohorts. This issue motivated me to develop a cost-efficient approach to discover cell-phenotype biomarkers, using both high-resolution single-cell and low-cost bulk genomic technologies. I will develop novel statistical methods and software tools for this novel approach. The key deliverables are: 1) an experiment protocol, novel statistical methods, and the first software pipeline for cost-efficient deep-phenotyping of large clinical cohorts, to discover biomarkers for ANY diseases; 2) novel AM phenotype biomarkers as drug targets of immunotherapy for COPD or a genomics diagnostic test (medical device) to guide personalized COPD treatment.

Targeting efferocytosis to reduce risk of cardiovascular events

Heart attack and stroke are the leading causes of death in Canada. These lethal events are caused by diseased cells accumulated on the wall of the blood vessels, leading to narrowing of the arteries. Although diseased cells can be removed naturally, this process is inhibited by inflammation. Recently, anti-inflammatory drugs are being actively developed to reduce heart attacks, but we lack methods to assess their effectiveness before testing in patients. This problem led to the failure of several clinical trials and serious side effects due to non-specific inhibition of the immune system. We will use models that closely mimic the conditions of patients and apply a thorough “onsite inventory” of diseased arteries to: 1) understand how inflammation inhibits the removal of diseased cells; 2) see if current drug candidates can neutralize these adverse effects in diseased arteries; and 3) explore and develop markers that can find patients who will benefit from the drug candidates. This study will provide evidence to guide the design of more specific anti-inflammatory drugs and their application to the right patients. It will minimize side effects and allow more patients to be properly treated to prevent heart attacks and strokes.

Developing sensors for rapid detection of biomarker proteins for Alzheimer’s disease

Dementia is a growing health challenge that affects over 500,000 Canadians today, which is estimated to grow to 900,000 by 2030. Alzheimer’s disease, the most common form of dementia, is characterized by protein misfolding in the brain. This process can start over a decade before the occurrence of significant cognitive decline making it possible to diagnose at an early stage when treatment strategies are most effective. Biomarkers are measurable indicators that help determine if a person may have or be at risk of developing a disease. Researchers have identified phosphorylated tau (p-tau) proteins and small proteins called cytokines to be promising biomarkers for Alzheimer’s disease. To detect these biomarkers in blood samples, very sensitive detection methods are needed but existing methods have drawbacks such as being expensive and time consuming, and need to be performed in a laboratory, limiting their availability to Canadians. We have developed a new sensor that can detect proteins at ultra-low concentrations using a simple and rapid test. Our goal is to make a rapid and easy-to-use tool that can be used by clinicians to help diagnose Alzheimer’s disease and patients for personalized health monitoring.

The links between nutrient sensing, cell intrinsic metabolism and T cell function in immune-related diseases

Our focus is on the cellular fuels and building blocks that change immune cell functions. Our immune system normally defends us against infections. In a healthy person, T cells (a type of immune cell) recognize infected or cancerous cells and remove them from the body. Normally, immune cells know the difference between healthy and infected or cancerous tissues. When this recognition is lost, it can lead to the development of attack of healthy tissues by immune cells (autoimmunity), the growth of cancer, or to persistent infections. This dysfunction of the immune system can lead to devastating diseases in children. My research aims to better understand how this happens. By comparing the way that biological fuels (sugars, fats and other building blocks) are used by immune cells from healthy people and patients with immune system associated diseases, we will define the cellular the pathways that maintain health or cause disease. This will allow us to target and “dial down” pathways that are driving cells to attack our tissues, or turn these pathways on to help immune cells fight persistent infections and cancerous cells. Ultimately, we hope to help develop new treatments.

Improving access to culturally safe, gender affirming, and trauma-informed abortion services and support for Indigenous women, Two-Spirit and LGBTQIA+ people in Canada

While Canada is currently one out of four countries globally to have no national restriction in law, the 2016 UN Human Rights Commissioner’s report indicated a lack of access to abortion due to cost, knowledge, and geography. For Indigenous Women, Two-Spirit, and LGBTQIA+ people in Canada, additional barriers exist including colonialism and racism. Yet there is an alarming gap in the literature surrounding Indigenous peoples and abortion services — despite knowing that one in three people in Canada will experience an abortion in their reproductive lifetime. The goal of this program of research is to build on existing community knowledge and strengths, advance knowledge around, and remove barriers to abortion services for Indigenous Women, Two-Spirit, and LGBTQIA+ people in Canada. Guided by an Indigenous feminist framework that acknowledges the intersectional experiences of Indigenous women, Two-Sprit, and LGBTQIA+ peoples and abortion access, this program of research will apply an Indigenous methodology to investigate experiences, gather knowledge, and co-develop resources to improve the abortion access gap among Indigenous peoples.

Examining motor imagery-related brain function in health and after stroke to leverage its prescription

Many stroke survivors (~85 percent) in Canada experience long-term impairments in arm and hand function. To aid recovery, motor imagery (the mental rehearsal of movement) shows promise as an adjunct therapy. Yet, its effectiveness is varied. We think this is due to a lack of basic knowledge about how motor imagery works. Motor imagery is thought to work similarly to physical therapy, whereby repetitive physical practice drives changes in brain function necessary for learning and recovery. However, we do not know a lot about how motor imagery drives changes in brain function. Using a blended approach not yet taken, we will examine changes in both brain function and behaviour driven by motor imagery. Importantly, we will examine how changes in brain function are altered and can be optimized after stroke, to improve its effectiveness. Findings will provide new information about how motor imagery should be applied to maximize learning and recovery, directly informing its use and prescription in stroke rehabilitation. Overall, this research represents a critical step in improving interventions for stroke recovery, leading to improved daily function and better quality of life for Canadians living with stroke.

Valvular heart disease and bioprosthetic heart valves: Defining mechanisms of degeneration and therapeutic discovery from bedside to bench

Aortic stenosis (AS) is a narrowing of the valve that controls blood flow from the heart to the body. AS results in significant decline in quality of life and can be fatal if untreated. Unlike most types of heart disease, there is no medication to treat AS and the primary therapy option is replacing the diseased valve with an artificial one by open-heart surgery or transcatheter implantation (insertion of an artificial valve through the blood vessels leading to the heart). Unfortunately, artificial valves can be dysfunctional and have limited durability, which can lead to heart failure, the need for repeat valve replacement, or death. With a focus on clot that can form on artificial valves, this research aims to determine the causes of valve dysfunction and degeneration, define methods to detect and predict which patients will experience valve dysfunction, and identify methods to increase valve durability. Overall, this work will provide critical new information to guide clinical care and the future evolution of artificial heart valve use that will improve the outcomes and quality of life of patients with AS.

Risk and protective factors for cognitive health across the adult age span: Impacts of physical and mental health and illness on cognitive outcomes

The virus causing COVID-19 can invade the brain, raising concern over long-term impacts on thinking abilities. We aim to identify long-term impacts on these cognitive abilities in those who have had COVID-19, and pinpoint factors that predict long-term outcomes. Adults positive for COVID-19 and those with no evidence of infection, are completing a series of cognitive and psychological tests in a current study. The proposed project will follow these individuals over time, with one and three-year follow-ups to examine changes in cognition across time. We will examine group differences in cognition, mental health, and other factors at each time point, determine if one or more cognitive profiles (clusters) characterize COVID-19 positive individuals, examine changes in these profiles across time, and test a screening measure to detect these cognitive difficulties. Findings will inform clinicians (e.g. neurologists, rehabilitation specialists) on trajectory of recovery of function and inform healthcare service provision in BC. Results will help ensure long-term impacts of infection are appropriately addressed, so those affected can efficiently resume complex activities requiring cognitive effort (e.g. employment, academic pursuits).

Self reactivity as a driver of extranodal diffuse large B-cell lymphoma transformation and survival

Lymphoma is a form of cancer that affects immune cells called lymphocytes, a type of white blood cell. There are many subtypes of lymphocytes and lymphomas. Diffuse large B-cell lymphomas (DLBCL) develop from B lymphocytes (B-cells) and are the most common subtype of non-Hodgkin lymphoma. About one third of DLBCL extend beyond the lymph nodes (“extranodal DLBCL”), and invade vital organs such as the kidneys, lungs, and brain, with an often-fatal outcome. Our ability to predict which patients will develop extranodal DLBCL is limited, and we also lack disease-specific treatments, partly due to an incomplete understanding of how and when these tumors originate. Interestingly, recent evidence suggests extranodal DLBCL share features with autoimmune disorders — conditions in which lymphocytes abnormally react against organs in our bodies, instead of external foes. In this study, we will investigate the relationship between the origin and progression of these diseases, in an effort to better understand how B-cells transform into cancerous cells, disseminate, and expand. Our work could help identify patients at high risk of developing extranodal DLBCL, and unveil key tumor dependencies to be leveraged as specific therapeutic targets.

Post-transcriptional regulation of hematopoietic stem cell function during normal and malignant hematopoiesis

In 2016, there were approximately 22,510 Canadians living with leukemia and an estimated 2,900 Canadians died from leukemia. Acute myeloid leukemia (AML) is one of the most common types of leukemia in adults. About 30 percent of AML patients eventually relapse after treatment and suffer from very poor overall survival at this stage. It is postulated that leukemia stem cells (LSCs), a small population of leukemia cells characterized with regenerative ability, mediate resistance and relapse after therapy. My work sought to uncover the largely unknown role of the processes that control protein generation in maintaining blood stem cells and how it contributes to transformation of leukemia stem cells in cancer. This research program aims to identify new factors, which can serve as targetable molecules and pathways to specifically eliminate leukemia cells while sparing normal cells. The work will provide the scientific foundation for future developments of therapy targeting these pathways as a novel strategy in eradicating leukemia stem cells to improve outcomes in AML patients.