Cytomegalovirus (CMV) is a virus that is present in 50-90% of adults globally, depending on the region. When a woman either becomes infected for the first time or reinfected during pregnancy, she may pass the infection to her fetus, which often causes hearing loss and intellectual disability in the child. CMV is the most common congenital infection worldwide. Women usually become (re)infected with CMV from virus shed by young children but a better understanding of how children transmit CMV to mothers is critical for designing strategies to prevent congenital CMV.
We aim to determine how much shedding of the virus in saliva and urine of young children is required to transmit the infection to their mothers and what strains of virus successfully infect. To achieve this, we will collect samples from new mothers and their children for 1 year in Nairobi, Kenya, where rates of CMV infection are very high. Statistical testing will be used to evaluate risk factors for child and maternal (re)infection with CMV.
This research project will provide invaluable information on CMV transmission and will inform the development of a vaccine to prevent maternal (re)infection and the resulting harm to children from congenital CMV infection.
One in eight Canadians suffers from osteoarthritis (OA), a debilitating joint disease that frequently includes bone bruises, known as BMLs. The question we want to answer is, do BMLs result from changes in muscle strength and coordination, or poor condition of ligaments (connecting tissues) or cartilage (smooth joint lining) that cause the cartilage loading to increase? This study investigates whether BMLs might be a result of the loading environment of the knee. Though the exact cause of these bruises is not known, they have been linked to increased pain and worsening of OA. This study will measure the size and location of BMLs in people with OA and relate them to cartilage contact and stress (loading over an area). A unique standing Magnetic Resonance Imaging Scanner (MRI; i.e., looking inside the body with powerful magnets in an upright position) will be used to image OA patients during a knee bend. The BMLs will be mapped over the contact areas and stresses. Findings will provide insights into what positions (e.g. depth of a knee bend) yield contact and stress closest to the BMLs. If BMLs are linked to loading, clinical changes can be made to loading (e.g., bracing) or drugs may be taken to intervene.
Osteoarthritis is a painful joint disease and leading cause of disability that affects over 6 million Canadians. The knee is one of the most commonly affected joints. Knee osteoarthritis (KOA) starts with mild joint pain and stiffness that worsens to extreme pain, often requiring surgery if left untreated. Being able to identify people with KOA in primary care at an early stage of disease would help promote less invasive treatments. Yet, primary care clinicians report many barriers to identifying and treating KOA. The proposed study works with primary care clinicians and their electronic medical records to identify patients with KOA. I will examine the prevalence of KOA across Canada and learn about KOA risk factors like previous joint injury and obesity. As well, the management approach of primary care clinicians for KOA patients will be analyzed. Lastly, a secure online KOA dashboard will be pilot tested in a small group of primary care clinicians. This dashboard will combine the electronic medical record data with patient-selected patient reported outcome measures (PROM) on pain, symptoms, physical activity, and quality of life to inform primary care clinicians and guide their treatment for KOA patients.
Many neurodegenerative disorders are characterized by the accumulation of proteins forming toxic aggregates inside neurons. Certain proteins contain regions with repeated amino acids that can favor the aggregation process. In the cell, the molecular chaperone system maintains a fully operational protein environment by helping proteins reach and retain their final structure, prerequisite for their functionality. However, two chaperones (DNAJB6b and DNAJB8) were recently identified to also prevent protein aggregation and prolong the lifespan in Parkinson´s and Huntington’s disease mouse models, making them interesting potential therapeutic targets.
Our goal is to identify which proteins inside the cell require DNAJB6b and DNAJB8 for proper folding. We will identify the “client” proteins of the two chaperones by using protein mass spectrometry and biochemical methods. The validation of the newly found interactions, together with the determination of a pattern recognized by the chaperones, will allow the potential design of new therapies for the treatment of amyloid-based neurodegenerative diseases.
Impaired arm and hand function after stroke (~85% of stroke survivors in Canada) is linked to altered brain activity and overactive brain areas. Practicing a task drives changes in brain areas important for function. Changes in these brain areas lead to recovery. But, overactive brain areas impede recovery. We can temporarily turn down overactive areas with brain stimulation to aid recovery. By targeting general brain areas important for movement, this non-invasive, painless approach shows promise. Yet, its response is varied. We think this is because overactive brain areas differ across individuals after stroke. We will target brain areas for stimulation on an individual basis to improve effectiveness – an approach not yet taken. The proposed work will 1) determine areas for stimulation after stroke by examining brain activity on an individual basis, and 2) pair individualized stimulation with task practice to aid recovery after stroke. We will show that improvements in hand and arm function are maximized when stimulation is tailored to the individual. This work 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.
Globally, persons living with HIV are aging, with women constituting over half of this group. Increasingly, women living with HIV (WLWH) are entering menopause, a crucial transition with impacts on overall health and well-being. Regrettably, there is limited research focused on how WLWH experience menopause, leading to a major gap in their quality of care. Preliminary studies suggest that WLWH may experience menopause with heightened symptoms. However, uncovering the true extent of this important relationship awaits detailed clinical analysis. Therefore, we undertake an interconnected set of aims to better understand the progression of menopausal symptoms within two Canadian cohorts of WLWH. For the first time, we evaluate how symptom severity progresses during the menopausal transition in this group. Subsequently, we assess whether hormonal imbalance underlies the increased severity of symptoms experienced in menopausal WLWH. Finally, we evaluate the clinical use of hormone therapy to treat these women which we predict is under prescribed for WLWH. By uncovering unique aspects of menopausal management in HIV, this work will enable development of tailored approaches to improve care for this vulnerable population.
Synovial sarcoma (SS) is the most common soft-tissue cancer among young adults. It is an aggressive tumor type in great need of new treatment options. SS tumors are defined by a specific genetic change that causes two separate genes to fuse into one. This new fusion-gene produces the SS18-SSX protein which is thought to remodel the cells epigenome, resulting in the activation and inactivation of a large number of genes. As SS18-SSX cannot be inhibited by any known drugs, we aim to identify the genes and regulatory elements that are directly affected by the protein. We have developed a novel SS mouse model and collected a large series of human tumors in order to study the effects of SS18-SSX in the context most relevant to patient. We will then use state-of-the art approaches to identify and disrupt the most important changes caused by SS18-SSX with the goal of identifying new treatment options for patients with this deadly disease.
Breast cancer (BCa) is the most common cancer and the second cause of death from cancer among Canadian women. While antiestrogens are effective initially, BCas eventually reach a state where they no longer respond to conventional treatments. In a first effort to develop new drugs for resistant BCas, we developed inhibitors with a novel mechanism of action, able to suppress the proliferation of BCa cell lines that do not respond to standard therapies. While promising, better compounds are required for effective treatment of resistant BCa.
Chemical libraries already contain more than one billion of compounds, starting a new era of computer-aided drug discovery. Unfortunately, screening of such amount of chemicals is not yet possible using standard methods due to the required computational resources. To overcome this limit, we have developed an artificial intelligence method, progressive docking, which allows to virtually screen such libraries for the first time ever. In this way, we will be able to discover new inhibitors by evaluating billions of available compounds, in order to improve the outcome of BCa for women in Canada and worldwide.
Our hearts play a crucial role to distribute blood throughout our bodies. When it beats irregularly, also called an arrhythmia, it can lead to major fatigue, loss of consciousness, or even death in some of the most serious cases. Arrhythmias can either be acquired throughout our lives or have genetic forms. The latter are more rare, but are usually more severe and affect very young people. In this project, we study a genetic form of arrhythmia that is due to mutations in a gene encoding "RyR2". RyR2 is very large protein that is present in all of our heart muscle cells, and its function is critical for the heartbeat. In particular, it allows calcium ions to move inside the heart muscle cells to maintain regular heartbeat patterns. The mutations, found in various families worldwide, affect the RyR2 protein directly, such that the calcium ions move too easily. We aim to understand how this happens, by solving the 3D structures of the ‘normal’ RyR2, and of RyR2 with a disease mutation. This comparison will allow us to look at the precise effect of the mutation on the structure of RyR2 and on how it functions. The 3D structures will also help with generating novel drugs that can help treat arrhythmia.
Prostate (PCa) and breast cancer (BCa) are leading causes of cancer deaths. These tumours depend on sex hormones that function through receptor proteins for their growth. For this reason, hormone therapies inhibiting these receptors are the first approach for controlling metastatic disease. However, hormone therapies eventually fail. Therefore, understanding how receptor proteins promote cancer growth will affect our approach for designing effective treatments for PCa and BCa.
Recently, we showed that sex hormone receptors activate Gli proteins in PCa and BCa cells. Gli proteins are regulators of genes that control cell growth and overactive Gli proteins cause brain and skin cancers. I propose that hormone-activated Gli is responsible for the growth effects of sex hormones in PCa and BCa. My work will characterize the relationship of sex hormones, Gli proteins and cancer cell growth. In addition, I will employ a novel technique to understand binding of Gli proteins with sex-hormone receptors and develop a new strategy to block cancer cell growth. This project will lead to a breakthrough in our understanding of sex hormone receptor action in PCa and BCa and evaluate a new approach to control the growth of these deadly diseases.
