Female reproductive decline (indicated by rising rates of infertility, birth defects, and miscarriage) is an early sign of aging, and is largely due to deteriorating quality of oocytes, or egg cells. Identifying the signaling pathways and mechanisms that control oocyte quality and reproductive decline is essential for better addressing female reproductive health issues, and can also provide key insights into other aspects of aging.
Our research focuses on the ties between nutrients, reproduction, and aging. In organisms ranging from worms to humans, signaling pathways that detect nutrients — such as the insulin signaling pathway — seem to play crucial roles in coordinating metabolism, reproduction, and lifespan. We will use a mouse model of genetically reduced insulin to determine how lowering insulin affects oocyte quality and reproductive success during aging. We will also study how insulin levels determine features of polycystic ovary syndrome, a common hormonal disorder, and evaluate long-term consequences of temporary nutrient excess or depletion.
We anticipate that this research will inform effective strategies to better manage female reproductive health, as well as to improve health during aging.
Proper myelination allows for the fast, efficient transmission of nerve impulses which is important for the coordination of movement, integration sensory information and cognition functions. In the brain, oligodendrocytes are the cells that extend numerous processes that wrap nerve cell (neuron) processes in a compact myelin sheath.
The overarching goal of my research program is to delineate the cellular mechanisms that underlie myelination across an organism’s lifespan. Several interconnected research projects investigate different aspects of how myelination occurs in the brain, such as the regulation of gene expression in oligodendrocytes, the cellular communication between oligodendrocytes and neurons, and the impact of environmental factors. These projects use animal models to investigate these biological questions at the molecular level (e.g. DNA, RNA, proteins and lipids). New insights into how these molecules interact to regulate myelination has broader implications for brain development, aging and pathology. This will ultimately lead to better health outcomes for persons living with neurological disorders.
Neurodevelopmental and fertility disorders represent significant health burdens in Canada, as approximately 1 in 66 Canadian youth are diagnosed with an autism spectrum disorder, and 1 in 6 Canadian couples experience infertility. Neurons and reproductive cells (oocytes and sperm) rely extensively on a form of control of gene expression called translational control. Mutations in the translational regulatory gene Fmr1 underlie the fragile X disorders known as fragile X syndrome (FXS) and fragile X primary ovarian insufficiency (FXPOI), which are leading causes of autism and premature ovarian failure respectively.
The proposed research will build upon my recent discoveries of Fmr1’s role in promoting the translation of genes encoding large proteins — many of which are associated with autism — in order to understand the mechanism by which Fmr1 activates translation. Knowledge of this mechanism will be of immense clinical value, enabling the development of novel therapies for citizens of British Columbia experiencing a fragile X disorder or related autism spectrum or infertility disorder.
T cells patrol the body using their T cell receptors (TCR) to look for cells which display evidence of intracellular pathogens or cancers. In order to focus their attention on specific cancer antigens, T cells can be engineered to express an artificial recognition receptor (termed a Chimeric Antigen Receptor or CAR). CAR technology has been shown to be extremely powerful clinically in leukaemia and lymphoma patients who have not responded to other lines of therapy, leading to recent FDA and Health Canada approvals.
However, only one third of lymphoma patients treated with CD19 specific CAR T cells exhibit long lasting curative responses, thus leaving significant room for improvement. CAR T failure can usually be attributed to either loss of the tumour antigen (ie CD19) or to dysfunction of the T cells, and we are developing a strategy to address the latter. Once T cells express a CAR, they can still receive signals through their TCR, and we have shown in preliminary experiments that this type of stimulation can help CAR T cells to proliferate and kill tumour cells. Our research will use oncolytic cancer killing viruses, and other vaccines, to help mobilize CAR T cells which recognize viral antigens using their TCR.
Antibody therapies have revolutionized modern medicine: they offer highly specific and effective treatments, with applications in oncology and rare diseases. The drawback of current antibody therapies is that they are expensive and must be administered intravenously, which limits widespread use. RNA-based gene therapy is a potential way to encode antibodies to make these treatments more universally affordable and accessible. For example, RNA-based gene therapy is used in the leading COVID-19 vaccines because it is easy to produce rapidly and cost-effectively at large scales. While RNA vaccines or protein replacement therapies have been widely investigated, the application to RNA-encoded antibodies is still in the early development phase. The main challenge is delivering sufficient amounts of RNA to target cells and ensuring the duration of antibody expression is therapeutically relevant. We aim to use self-amplifying RNA (saRNA), a type of RNA that replicates itself in cells, to encode antibodies. saRNA results in higher protein expression than normal RNA using a lower dose of RNA. We hypothesize that by optimizing the formulation saRNA will enable a low-cost, easily administered approach to antibody therapy.
Stem cells offer tremendous potential for tissue regeneration and uncovering causes and treatments for many human diseases. Technologies developed over the past decade now allow us to grow human stem cells in the lab and manipulate them to carry disease-causing gene mutations and turn them into any cell type of interest. My lab’s research uses these powerful tools to identify important regulators of stem cell function, particularly as they develop into cell types relevant to brain disorders. We focus on identifying the biological processes that build our brains, and biomarkers and treatment approaches for diseases.
Though the genes that regulate stem cell function are fairly well know, the impact of cell organelles, which coordinate many biological functions and are potential targets for treatment, is poorly understood. My lab is working to bridge this gap by investigating the impact of vesicle-like organelles called lysosomes on brain stem cells. Our data suggests lysosomes are critical regulators of stem cell function and brain development. Given new imaging-based tools and clinically approved lysosome-targeted drugs, studying the role of lysosomes can transform our potential to understand, diagnose, and treat brain disease.
Although researchers have identified tens of thousands of disease-associated genetic variants, the mechanisms driving most of these variants remains unknown. Most variants are believed to affect regulatory elements. However, regulatory elements are incompletely annotated and understood. Large-scale projects have recently generated thousands of epigenomic data sets. These data sets measure the regulatory activity of the genome in human cells. However, computational methods are needed to understand the link between genetic variation and disease.
We previously developed a computational method, Segway, that annotates genomic regulatory elements on the basis of epigenomic data sets. Enabled by new epigenetic data sets, this project will annotate the genome in hundreds of human cell types, and use these annotations to understand disease-associated genetic variation.
Additionally, we will develop computational methods that improve our ability to identify genomic elements. This outputs of this project will come in three forms:
- General-purpose software for annotating the genome.
- Easy-to-use reference data sets.
- Insights into the link between genetic variation and chronic obstructive pulmonary disease (COPD).
Neurodevelopmental disorders (NDDs) impact 7 to 14 percent of all children in developed countries. NDDs are incredibility heterogeneous and are caused by a complex interaction of genetic and environmental risk factors. One of the most consistent findings across NDDs is altered immune function, but it is unclear if neuroinflammation is a cause or consequence of brain pathology. My laboratory will directly test for causality and identify the optimal mechanisms and timepoints for immune based interventions in NDDs. Targets and compounds that impact microglia, the main immune cell in the brain, have immense potential for treating a broad range of NDDs.
Under normal healthy circumstances our intestines are home to hundreds of species of microbes, collectively termed the microbiota. Our intestines can also be colonized by parasites, such as parasitic worms (helminths). Both the microbiota and helminths can affect the functioning of our immune system, which in turn, can influence our susceptibility to a variety of infectious, allergic, and inflammatory diseases. Research in my laboratory is focused on understanding the mechanisms by which helminths and the microbiota affect immune system functioning during normal development and during states of disease.
The incidence of allergies and inflammatory bowel diseases has increased dramatically in Canada over recent decades, and there is an urgent need both to understand the factors driving disease development and to identify new treatment strategies. My laboratory uses the mouse model system where the molecular mechanisms of interaction between components of the immune system, the microbiota, and helminths can be identified. Understanding the mechanisms by which the microbiota and helminths can influence immune system functioning may reveal new ways to treat or prevent allergic and inflammatory diseases.
Mosquitoes are the deadliest animals on the planet. Many species use sophisticated sensory systems, including smell and taste, to locate human beings and other animal hosts in their environment as a source of blood. When they blood-feed, they can transmit microorganisms that cause human diseases including malaria and dengue fever. After converting a blood-meal into eggs, a female mosquito must find an appropriate body of water to lay eggs where her offspring will thrive. Selecting an egg-laying site is an important part of the mosquito lifecycle, since the juvenile larval and pupal stages are aquatic and cannot move from where they hatch. Mosquitoes do not fly far, and so their choice of breeding site strongly influences where they can be found as adults and thus, where they can transmit disease.
The goal of my research is to understand how mosquitoes use their sense of smell and taste to make decisions about who to bite and where to lay eggs. I use techniques to modify their DNA and to look at the activity in their brains under a microscope. Ultimately, this research will help us understand why some mosquitoes are more deadly than others and provide the basis for mosquito control strategies such as traps and repellents.
