Spinal cord injury leads to permanent and severe paralysis and loss of sensation. The principal reason for this is that nerve cells connecting the brain with the rest of the body lose the capacity to regenerate their processes (axons) as they mature during development. Despite decades of progress, no regenerative therapy for the injured spinal cord is available today, making a regenerative treatment for spinal cord injury a major unmet need of the British Columbia healthcare system. In this project, we will focus on the fundamental processes through which maturation suppresses axon regeneration. We have discovered a molecular switch that is turned off in mature neurons and that we hypothesize is critical for nerve cells to regrow axons. We will study how this molecular switch is turned off during maturation, the processes that it controls to enable growth and test whether re-activating it in mature neurons can promote regeneration and functional improvements following spinal cord injury. Collectively, this work will provide critical insight into why mature nerve cells fail to regenerate. We anticipate that this work will be a major steppingstone towards the development of a treatment that regenerates the injured human spinal cord.
Research Pillar: Biomedical Research
Development of Metabolomics to Interrogate the Effects of Maternal Sugar Overconsumption on Pregnant Rats and Their Offspring
Sugars such as sucrose (table sugar) are extremely common in the diet, in Canada and across the world. The World Health Organization advises that added sugars should make up 5% or less of daily calories for adults, and even less for children under 2 years. However, in Canada, adults and children often greatly exceed these recommendations. Of particular concern, added sugars during early development might have major and long-lasting effects on hormones, neural circuits, and behaviour. Our work is to develop sensitive and robust metabolomics technology to identify the key sugar products and other chemicals that play a key role in this biological process. This work allows us to understand the molecular basis between sugar intake and the long-lasting effects on adult offspring. The results will have important implications for the health of Canadians because very little is known about how mother’s sugar intake affects the baby health and diseases.
The oxygen cascade as a therapeutic target in humans with hypoxic-ischemic brain injury
During a cardiac arrest the heart stops beating and blood flow to the brain stops, starving the brain of oxygen and causing a brain injury. In resuscitated patients whose heart starts beating again, this brain injury is the number one cause of death. As no therapies are available to treat this brain injury, my research will determine ways to improve the treatment of post-cardiac arrest patients with a brain injury. My research will use measurement probes placed directly in brain tissue as well as the analysis of blood entering and leaving the brain in humans to: 1) determine how to restore optimal oxygen levels in the brain; 2) develop tests to identify patient specific factors underlying low brain oxygen levels that can then help guide personalized patient care; and 3) investigate the molecular mechanisms of this brain injury. This work will be foundational to the development of new therapies to treat brain injuries caused by low oxygen levels in the brain. By determining widely implementable techniques to identify how oxygen delivery is impaired at the bedside, we will be able to tailor care in central and rural settings within British Columbia and provide patients with the specific treatments that work best for them.
Advanced multi-functional in vivo retinal imaging for ocular oncology
Ophthalmic imaging plays a crucial role in the evaluation, follow-up, and treatment decision-making in ocular oncology. This critical role is even more prominent when dealing with the early-stage choroidal melanoma or amelanotic tumor patients, in which diagnostic uncertainty is especially prevalent. This is due to the significant overlap in the clinical and imaging findings of benign and malignant choroidal tumors. Current imaging modalities are not helpful in reliably differentiating the malignant features in suspicious choroidal lesions and often require long-term serial follow-up that places a significant burden on patients and providers. Recent studies have shown that melanin alternation in the choroid is correlated to the malignancy and metastasis potential in choroidal tumor patients. The main goal of my research is to develop a novel high-resolution, molecular-specific clinical ophthalmic imaging system to visualize and quantify the melanin contents in choroidal tumor. This research outcome will provide important diagnostic clues in the evaluation of choroidal tumors, facilitating early non-invasive identification of high-risk features of malignancy.
Improving genomic epidemiology methodologies and practice through interdisciplinary data integration and analysis
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.
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.