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.
Program: Trainee
Severity and Treatment of Menopausal Symptoms in Women Living with HIV
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.
Characterization of Pathogenic Chromatin States in Synovial Sarcoma
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.
Redevelopment and Optimization of an Adeno-Associated Virus Gene Therapy Product for the Treatment of Lipoprotein Lipase Deficiency
Lipoprotein lipase (LPL) is an enzyme that breaks down fats, specifically triglycerides, in the blood. An individual with LPL deficiency, which is cause by a defective gene, will therefore begin developing high triglyceride levels as a child. In time, they will develop life-threatening pancreatitis, a predisposition to heart disease, and ultimately, an increased risk of mortality. Previously, we developed a gene therapy for LPL deficiency that was shown to be safe and effective in clinical trials. In 2012, marketed as Glybera, this treatment became the first gene therapy product in the world to receive regulatory approval. However, its extremely high price (>$1 million/patient) severely limited its use, and in 2017 Glybera was removed from the market. Patients now have no curative treatment for LPL deficiency. A major contributor to the therapy's high cost were the small-scale production methods. As part of the Hayden and Ross lab and in collaboration with the National Research Council of Canada, the aim of my project is to develop and validate a more efficacious and cost-effective Adeno-Associated Virus (AAV)-based gene therapy treatment for LPL deficiency.
Artificial intelligence based discovery of estrogen receptor activation function 2 (AF2) inhibitors as the first-in-class therapies for drug resistant breast cancers
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.
B cells: New players in the immune response to cancer
High-grade serous ovarian cancer is an aggressive disease with a low survival rate (~30%). Patients who survive longer mount strong antitumor immune responses as evidenced by the recruitment of immune cells to their tumors. Among those tumor-infiltrating immune cells, B cells that produce antibodies are particularly prognostic, yet poorly studied. We still do not know how B cells help to control tumor growth.
Using a technique that captures gene expression with single-cell resolution, I will profile immune cells isolated from 50 ovarian tumor specimens. I will then leverage these single-cell gene expression profiles (i) to identity prognostic B-cell subpopulations and (ii) to determine how B cells interact with other immune cells to ultimately eliminate tumor cells. Next, I will isolate the antibodies produced by tumor-infiltrating B cells and use these antibodies to define what B cells recognize on tumor cells.
My findings will provide unprecedented insights into the inner workings of the immune system in patients, informing the design of new immunotherapies that boost antitumor immunity and promote long-term survival of patients.
The Role of Microglia in Chronic Stress-Induced Cognitive Impairment
Chronic stress is associated with cognitive impairment. It is possible that this is due to the brain's immune cells, microglia. Microglia can engulf and chew up neurons, which are the cells in the brain that talk to one another. It is possible that chronic stress makes these immune cells more likely to engulf neurons, which leads to cognitive deficits. To understand this, we will use live imaging to look at how microglia act in the brain of chronically stressed laboratory mice. We will then see if treatments that can reverse chronic stress induced cognitive deficits, such as probiotics, cannabinoids, omega-3 supplementation or ketogenic diet, work through altering these brain immune cells (microglia). Together these data will better inform how chronic stress leads to alterations in cognition and may provide a new target for therapeutics of cognitive deficits observed in stress-associated disorders, including depression and anxiety disorders.
Developing novel therapeutic targets to treat arrhythmia-causing ryanodine receptor variants in the heart
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.
Characterization of Gli proteins as a novel therapeutic target in prostate and breast cancer.
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.
Understanding adaptability in egg-laying behavior in Aedes aegypti
Mosquitoes are the deadliest animals on the planet. Aedes aegypti mosquitoes are found in many parts of the world. When they bite people to take blood, they can transmit microorganisms that cause disease. One reason that Ae. aegypti is so deadly is that it is closely associated with people and can breed in a wide range of water-filled containers such as dumpsites, construction sites, and discarded plastic containers.
Ae. aegypti must carefully choose where to lay their eggs. These decisions are achieved by using different senses to detect water where their progeny can thrive. The aim of my proposal is to characterize the genes and brain circuits important for mosqutioes to identify optimal egg-laying sites. I will perform these studies across groups of Ae. aegypti that have distinct egg-laying preferences to understand how these mosquitoes have adapted to the wide variety of environments associated with people.
Ultimately, my work will help us understand why Ae. aegypti (and not other species of mosquitoes) have become so intertwined with us and, thus, are so deadly. These studies will provide foundational data to support critically important mosquito control efforts around the world.