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.
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.
Early childhood represents a critical period in which a child’s brain undergoes rapid brain development and is critical to later health and wellbeing. During this time, infants and young children have especially high needs, both for energy and key essential nutrients, when compared to older children and adults. Yet feeding and nutrition guidelines for infants and toddlers during this crucial developmental window remain poorly understood, explained in part by the major changes with regard to infant and toddler feeding practices in the past century.
Therefore, the specific focus of this project is understanding how feeding patterns (including breastfeeding, cow’s milk, and formula) in the first two years of life are associated with toddler cognitive development at 24 months of age. In particular, the research will focus on key nutrients recently identified as crucial for healthy development and function, but which are currently limited in toddler diets and guidelines. The study has clinical and public health implications for toddler nutrition and will help inform and clarify current toddler feeding guidelines in order to improve the health and development of Canadian children.
Pathological gambling is an addictive disorder characterized by repeated problematic gambling despite severe negative consequences, often linked to poor decision making and impulsivity. Research into gambling disorders has been facilitated by using rodent tasks that are directly translated from tasks used in humans. Traditional analyses for these tasks result in simplistic measures linked to decision making deficits and impulsive behavior. More recently in clinical research, computational modeling has been applied to data from human tasks to allow more sophisticated, in-depth analysis of the psychological and cognitive processes underlying these behaviors. Despite many parallels in task measures and structure, computational approaches are much less frequently used in the analysis of rodent behavioral data. Using multiple large datasets from rodent gambling and decision making tasks, this project proposes to use computational modeling to investigate the underlying cognitive processes involved in performance on these tasks. This will improve translatability of findings from preclinical research, and enable the generation of testable hypotheses for novel therapeutic/behavioral interventions to address problematic gambling behavior.
Studies have shown that vaccinating pregnant mothers protects both mothers and children. Yet, recent surveys suggest that one third of Canadian parents are unsure about vaccinating. Mothers often decide how they feel about vaccines during pregnancy, and healthcare workers play an important role in helping them make these choices. More and more new parents in Canada choose to give birth with the help of a Registered Midwife (RM). Unlike other healthcare providers, RMs, following the guideline of Informed Choice, encourage their clients to make choices for themselves using the best available information. Because of this, some RMs feel that they should not make a strong pro-vaccine recommendation. This research project will focus on creating midwife training resources that are compatible with the model of Informed Choice. Using interviews with midwives, educators, and professional associations, we will develop tools for continuing education adapted to the RM profession. By better understanding the challenges midwives face when talking about vaccines, this study will help RMs enable their clients in BC and Canada to make better informed decisions about vaccination.
End of Award Update: October 2022
Most exciting outputs
Our research aimed to better understand how midwives discuss vaccination in pregnancy (and infancy) with their clientele. Through interviews with midwives and other professionals we learned more about vaccine conversations in pregnancies and some of the related challenges. We published research showing how Informed Choice conversations aimed to inform and empower pregnant people about vaccine decisions and described what changes could be made to better support midwives who discuss vaccination and provide vaccines to their clients.
Impact so far
We have created a vaccine communication training module with the Continuing Professional Development program at UBC, which is available in French and English to midwives across the country. Our team also published results from our interviews in international peer reviewed journals to reach a wide audience.
Potential influence
Hopefully, this research has shed light on how midwives are capable vaccine counsellors, with the training and expertise to engage and inform vaccine hesitant populations.
Next steps
This research is being continued by my colleagues at the Vaccine Evaluation Center at the BC Children’s Hospital Research Institute. Our team is continuing to collect data to develop and test a clinical intervention package that will provide communication tools like pamphlets and informative videos to be used in midwifery clinics in Canada.
Useful links
Huntington’s disease (HD) is a fatal inherited neurodegenerative disorder caused by a single gene mutation. Most patients present with disordered cognition and movement in middle age due to striatal and cortical neuron degeneration. However underlying HD processes begin earlier and are incompletely understood. Although striatal projection neurons are most vulnerable, cortical pathology likely primarily drives cognitive dysfunction in HD and may impact striatum health via extensive cortical-striatal projections. Using voltage-sensitive dye imaging, we monitored the activity of cortical neurons in HD-model mice, where we found sensory-evoked signals spread more extensively. This suggests an excitation/inhibition imbalance, the details of which we are clarifying with additional experiments. Ultimately, the above could affect motor and cognitive performance in HD and contribute to neuronal toxicity mediated by excessive excitatory neurotransmission. This research furthers our understanding of early brain circuit changes in HD and how they contribute to neurodegeneration; hopefully these findings will inform future early HD treatment interventions. Results will also be published in scientific journals and communicated to the media.
Some of the lung bacteria protect the lung against bad germs. Tests have shown that people with sick lungs often do not have these ‘good’ bacteria in their lungs. Our team has shown that breathing air pollution causes the lungs to be irritated, leading to inflammation. Inflammation of the lungs can make it hard to breathe, especially for people who have lung problems. We think that polluted air could change the lungs’ bacteria. To understand this, we asked healthy volunteers and people with lung sickness called chronic obstructive pulmonary disease (COPD) to participate in a study. They sat in a room for 2 hours and breathed either clean air or air with diesel exhaust that is a model of air pollution like that found in big cities around the world (i.e. Mexico City, or New Delhi). A doctor checked them and took small samples of fluid from within their lungs. We will use these samples to examine the lung bacteria and evaluate the effect of these bacteria on lungs’ health. This study will help uncover how air pollution affects our lungs and bacteria that are inside the lung. This study will help doctors and governments make decisions about traffic-related air pollution and respiratory health.
Vascular cognitive impairment (VCI) is caused by cerebral small vessel disease and is associated with cognitive and physical impairments in aging. Cerebral small vessel disease can lead to different types of brain damage, including myelin loss. Myelin is critical for proper brain function because it allows different brain regions to communicate with each other and intact myelin is vital for optimal human function. It is crucial for us to measure myelin loss and understand how myelin loss may be associated with cognitive and physical outcomes in older adults with VCI.
The goals of this study are to: 1) determine whether myelin loss is associated with cognitive and physical function in VCI and; 2) determine whether myelin imaging is better than other imaging techniques at assessing cognitive and physical outcomes in older adults with VCI.
The results of this study will: 1) help us understand how myelin loss affects cognitive and physical function and; 2) help us determine whether myelin imaging can be used as an additional tool to monitor disease progression and assess the efficacy of clinical intervention studies.
