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.
Year: 2022
Making room at the table: Understanding the mealtime experiences of racialized residents and their families in long-term care
Mealtimes in long-term care (LTC) homes are important for visible minority (e.g. Chinese, South Asian) residents’ well-being and keeps them connected with their families who help at mealtimes. Visiting restrictions during the COVID-19 pandemic meant that some families could not provide mealtime care which had negative effects on residents and families. There is very little research on the mealtime experience for visible minority residents and families and even less on their experiences during the pandemic, even though almost one-quarter of Canadians are from a visible minority group. It is important to understand these experiences to improve mealtimes in LTC homes. This qualitative study will answer the question: what are the mealtime experiences of visible minority residents and their families in LTC? The objectives of this study are to: 1) understand the mealtime experiences of visible minority residents and their families; 2) understand how these mealtime experiences are impacted by social, political, and economic factors; 3) identify ways to improve mealtime care for visible minority residents and families; and 4) share the research findings with stakeholders to improve mealtime care in LTC homes.
Dissecting heterogeneity in COPD: A functional imaging-guided-omics study
Chronic obstructive pulmonary disease (COPD) is a common lung condition with no known cure. Understanding lung abnormalities in COPD is critical to develop new treatments. However, lung abnormalities in COPD are ‘patchy’, and test samples (e.g. biopsies) used for laboratory studies may not be from the most diseased areas. We will use advanced lung imaging techniques (magnetic resonance imaging (MRI) and computed tomography (CT)) to identify ‘high-disease’ areas in the lungs of volunteers with COPD, and take samples from these areas using a camera inside the lungs (bronchoscopy). We will take samples before and after treatment with a common antibiotic medication (azithromycin) and test for changes in lung genes. Our approach may ultimately help develop new treatments for the 384 million people worldwide who suffer from COPD.
Defining optimal pregnancy weight gain ranges for Canadian women
Maternal weight gain is closely monitored during pregnancy because as weight gain increases, so does the risk of excess postpartum weight retention, diabetes, and high blood pressure. While lower weight gain may prevent these complications, it also increases the risk of poor fetal growth and stillbirth. Pregnancy weight gain recommendations that balance these risks are important. The goal of this project is to establish the optimal range of pregnancy weight gain for Canadian women. We will use existing medical records from approximately 560,000 women who delivered in BC between 2004 and 2018. We will obtain information on pregnancy weight gain, and link this with short- and longer-term health complications for mother and newborn, such as excess postpartum weight retention, maternal diabetes and heart disease, poor fetal growth, and stillbirth. We will use statistical models that enable us to consider all health complications at the same time, while accounting for the fact that some complications are more serious than others. Our findings could provide the basis for new public health recommendations on pregnancy weight gain, which could help to reduce overweight and obesity in Canadian mothers and their children.
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.
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.
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.
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.
The impact of olfactory dysfunction on social and mental health
Our sense of smell enriches our lives—from enhancing pleasures (e.g. aroma of coffee) to signalling danger (e.g. smoke). Loss of smell is related to a range of social and emotional impairments, including elevated rates of depression, social isolation, and relationship difficulties. The COVID-19 pandemic causes transient smell loss, providing a novel opportunity to study one of our least understood senses. My first aim is to examine pathways linking olfactory loss to social and emotional impairments. I will recruit a prospective cohort of adults with recent onset of olfactory dysfunction and no flu-like symptoms (N=300) as well as a control cohort (N=100). Participants will be assessed over eight weeks, covering the typical period for olfactory recovery in COVID-19 patients. This data will provide a first-ever look at how within-person changes in olfaction relate to changes in social and emotional wellbeing. My second aim is to develop a brief, behavioral intervention by conducting a randomized trial focused on the benefit to participants from an online intervention. After refinement, this intervention will be offered freely, and findings will inform efforts to improve mental health for people with olfactory dysfunctions.
Determination of the optimal SARS-CoV-2 vaccination strategy to achieve a robust and long-lasting immune response
Global COVID-19 vaccine distribution has been inequitable, with high-income countries afforded widespread access to vaccines and boosters, while among the low-income countries only 2 percent of individuals are vaccinated. Consequently, over 50 percent of the world’s population remains unvaccinated. Fortunately, however, data from vaccinated cohorts can inform the most efficient and effective community-level vaccination strategies for the unvaccinated populations. Currently approved mRNA vaccines were initially tested with dosing intervals of 21-28 days; however, this may lead to suboptimal immunity. Further, data informing the optimal timing and frequency of booster doses is lacking. This project will answer critical questions regarding the optimal vaccination strategies to achieve a robust long-lasting immune response. In this study I will employ data from a prospective national cohort of adult paramedics, providing sociodemographic data and serum blood samples. I will identify the optimal vaccination strategies to achieving a robust immune response at 12, 18 and 24 months, including examining differences between sex, race, and age. These data will inform ongoing global vaccination efforts, to maximize efficiency and long-term protection.