Infectious diseases as shown by the COVID-19 pandemic, remains a serious threat. Genomic sequencing has revolutionized the detection and characterization of pathogens for surveillance and outbreak investigation, creating the new field of genomic epidemiology. During this ongoing pandemic, we have witnessed several gaps in establishing effective global responses that require coordinated action such as our ability to quickly adapt analytical methods to new pathogens and the ability to integrate several data sources to generate knowledge for enabling evidence-informed decision making. In this proposed research, I aim to further this field of genomic epidemiology by developing advanced data analysis methods. Additionally, I aim to optimize these methods to be capable of adapting to datasets from various pathogens, saving time to develop again for every outbreak. Finally, I want to combine genomics and advanced data analysis (bioinformatics) to establish a method of integrating epidemiological, political, and other contextual information with genomic data to improve public health preventive measures. This project will develop a program to use intersectoral genomic epidemiology for countering infectious diseases.
Research Pillar: Biomedical Research
Innate immune mechanisms of viral myocarditis: Role of the cytosolic DNA-sensing pathway
Coxsackie virus B (CVB) is the number one cause of viral heart inflammation leading to heart failure and sudden death in ~20 percent of infected children and young adults. In most people, CVB infection causes mild symptoms. However, individuals with underdeveloped and/or compromised immune systems are at increased risk of severe disease. Normally, our healthy immune system acts as a first line of defense against viruses, but excessive and sustained activation of our immune system can be harmful, leading to chronic inflammation and injuries to the heart. The objective of my project is to study how CVB hijacks a novel immune pathway called cGAS-STING, to trigger harmful inflammation in the heart. Our knowledge gap is that we do not completely understand how CVB hijacks the cGAS-STING immune pathway and whether blocking this pathway with drugs can protect the heart. To accomplish this goal, we will precisely identify which cells and immune pathways are responsible for harmful inflammation of the heart. Findings from this study have the potential to open new therapeutic avenues to combat existing and emerging viral threats.
Molecular determinants of pathogenesis and clinical outcomes in high-grade B-cell lymphoma
One-third of patients with aggressive non-Hodgkin lymphoma relapse after conventional chemotherapy and die of their disease. We need new methods to identify, at diagnosis, which patients have a high risk of relapse to improve their treatment. Genetic profiling is a powerful tool that can identify these high-risk patients. ‘Double-hit lymphoma’ (DHL) is one type of lymphoma that responds poorly to standard treatment. Current testing strategies cannot accurately identify all patients with DHL. We aim to improve the identification and treatment of DHL with a new test that uses a unique ‘genetic blueprint’. We will apply this test on lymphoma samples from 900 aggressive lymphoma patients in British Columbia to find out its ability to identify DHL patients compared to current methods. Patients who carry this genetic blueprint may benefit from different treatment approaches that overcome the high risk of relapse. We will also conduct an in-depth genetic analysis of DHL to understand how these lymphomas develop in the body. This new knowledge will help design smarter therapies that target the tumour while sparing normal body cells. These ‘targeted therapies’ can avoid the significant side effects caused by intensive chemotherapy.
Examining stress mediated profibrotic response in HCM associated TNNT2 variants
The heart beats 100,000 times a day, and cardiac contractile proteins are essential to facilitate oxygen-rich blood circulation. Hypertrophic cardiomyopathy (HCM) is an inherited heart disease that promotes enlargement of the heart and fibrotic scars, leading to arrhythmias and sudden cardiac death (SCD). In Canada, all age groups are affected by HCM, especially children and youth, including elite athletes. The cardiac troponin T (TNNT2) gene variants account for 15 to 20 percent of HCM in humans. TNNT2 mutations can cause increased cardiac contractility and impaired heart relaxation, leading to structural remodelling and triggering arrhythmias and SCD. Currently, no specific medication is available to treat HCM patients. Previously, mouse or rabbit heart muscle cells were used for studying these TNNT2 mutations, which is not closely relevant to human physiology. Therefore, I aim to test TNNT2 mutants in human induced pluripotent stem cell-derived heart muscle cells (hiPSC-CMs) with different physiological and pathological stress conditions compared to normal hiPSC-CMs. Our research outcome will help us refine the profibrotic mechanism behind arrhythmias and SCD in HCM patients and timely intervention to manage patient care better.
Mitotic bookmarking by transcription factors as a mechanism of transcriptional memory
Cells that are the building blocks of the organism come in different forms and functions. Stem cells are a unique type of cells, because of their ability to change (differentiate) or maintain their state. Because of this ability to differentiate into any type of cell, stem cells are on the frontiers of regenerative medicine, which is aimed to restore damaged cells, tissues or organs. The cell division (mitosis) poses a challenge for cell identity. During mitosis, the DNA is condensed into characteristic mitotic chromosomes, the nuclear membrane, separating DNA from rest of the cell, is fragmented, and the gene expression ceases. How then cells memorized which genes were expressed, to continue their expression after mitosis? The mitotic memory has been proposed as a mechanism for the maintenance of cell identity after mitosis. One arm of this mechanism, called bookmarking, is the binding of transcription factors (proteins regulating gene expression), to mitotic DNA. This project aims to establish the molecular mechanisms of mitotic bookmarking in mouse embryonic stem cells. Using methods, such as gene editing, genomics, and imaging, I will solve how stem cells maintain their identity after countless number of cell division.
Multimodal characterization and classification of bio-signals to predict cardiac arrest
Sudden cardiac arrest (SCA), due to abrupt disruption of cardiac function, is a major health problem globally. SCA can happen to anyone at any age who may or may not have been diagnosed with heart disease. SCA has a poor survival rate of about 10 percent, with an estimated 35,000 deaths in Canada annually. With an increasing rate of cases (16 percent from 2017 to 2020), SCA remains a major public health issue in British Columbia. The most effective strategy to improve survival is to achieve rapid SCA recognition, given that for every minute without cardiopulmonary resuscitation (CPR) survival rates drop by 10 percent. Wearable devices may play a major role in decreasing SCA mortality, providing real-time cardiac information for early SCA detection. My aim is to develop a wearable SCA device with embedded sensors, and use their real-time physiological data combined with artificial intelligence algorithms, to make an accurate SCA detection system. This SCA detection system will be designed to identify SCA and alert Emergency Medical Services with the individual’s location (via GPS), enabling them to provide life-saving interventions in a timely manner.
Evaluating the role and therapeutic value of Asparagine Endopeptidase (AEP) in prostate cancer
According to Canadian Cancer Society, one in eight men will be diagnosed with prostate cancer (PCa) in his lifetime. Most of the PCa initially respond to the treatment but eventually, some of the tumors become resistant and develop into an incurable disease. Mechanisms promoting the treatment-acquired resistance are still elusive. Our study exploring the alterations of global protein abundance unveiled an elevation of the Asparagine Endopeptidase (AEP) in the treated PCa cells, and repression of the elevation delayed cancer cell growth. AEP is a protease enzyme functioning in the cellular organelle lysosome to cleave and degrade specific substrate proteins. The role of AEP in the treatment resistance in PCa has not been investigated, we therefore propose to explore the mechanisms of AEP elevation upon the treatment and the role of AEP in cell division, cell death and cell spread under treatment stress. We also plan to develop small-molecule inhibitors targeting AEP to evaluate the co-targeting efficacy in combination with the conventional treatment approach. Our work may identify a novel mechanism promoting the treatment-acquired resistance and highlight AEP as a potential therapeutic target in PCa.
Roles of the Lysine Methyl Transferase (KMT) 2d in hepatocyte identity and hepatocellular carcinoma progression
Liver cancer is the third most common cause of cancer-related deaths globally, and patients with liver cancer currently have limited treatment options, including tumor ablation and liver transplant. More than half of the liver cancer cases have mutations in regulators of genome structure, which play a crucial role in cellular differentiation and development by controlling gene expression patterns. Lysine Methyl Transferases 2d (KMT2d) is one of the most frequently mutated regulators. However, we do not fully understand how changes in the KMT2d can drive liver cancer. In this project, I will investigate the mechanism in which KMT2d influences liver development as well as induces liver cancer from normal liver cells using organs that mimic human livers. Moreover, discovering its interaction partners, such as transcription factors that function in turning on and off genes, will provide more comprehensive mechanistic insight into the roles of KMT2d in liver formation and health. This study will advance fundamental knowledge for future research on the liver’s developmental biology and provide promising alternative therapeutic avenues for liver cancer.
A novel stem cell model for human islet development and cytoarchitecture
The cultivation of stem cells to insulin-producing beta cells offers an unlimited source of transplantable material for diabetes treatment. However, currently manufactured beta cells do not function precisely like the healthy ones in our bodies. Human islets are cell clusters mainly comprised of a mix of endocrine cell types, and interactions among them are critical in controlling insulin secretion. However, this point has been overlooked by current manufacturing methods that typically attempt to make clusters enriched only for beta cells. The absence of other islet cell types may therefore be a leading cause of the failure to obtain properly regulated insulin production. We recently developed a method to coax stem cells into islet clusters that are enriched for major endocrine cell types. Interestingly, these islets formed through an essential but unidentified “budding process” and self-organized into distinct cellular arrangements over time. Our goal is to elucidate the mechanisms that regulate islet formation, including the ways in which the cells assemble and impact islet function. Success could facilitate methods to manufacture islet cells with more robust insulin production and guide cell replacement strategies for diabetes.
Exploration through movement variability: How does the presence of pain affect the movement variability-adaptation process of walking?
When we walk, our bodies take each step slightly differently. This variability is how the brain explores movements so we can adapt to changing environments (e.g. bump in the sidewalk) or new challenges (e.g. painful motion). Pain from injuries or disease can lower this natural exploration because our brain avoids painful movements, ultimately limiting our ability to adapt. My study aims to understand how pain affects this variability-adaptation process in walking. In these studies, we will use electrical stimulation to create artificial knee pain, since naturally occurring pain fluctuates and is difficult to control. By synchronizing the painful stimulation with walking motions, we can precisely control the timing and severity of pain so we can measure the variability-adaptation process in real-time. First, we will test how knee pain changes movement variability. Then, we will measure how adaptation is affected by lower variability created by the pain. To conduct these projects, we will develop new wearable technology that combines electrical stimulation and motion tracking devices to perform this work in places outside the lab. The results will inform how movement variability can affect rehabilitation of painful conditions.