Type 1 diabetes (T1D) involves the loss of insulin-secreting beta-cells, the main cell type in the pancreatic islets. A special feature of beta-cells is that they must make large quantities of insulin protein, which is very demanding and leaves them vulnerable to stress. Stressed islets are less functional and may die. Islets from females appear more resilient than islets from males to stresses relating to insulin production. However, we lack knowledge on how female islet cells achieve this, and preclinical research rarely studies both sexes. This project will characterise the mechanisms that occur in male and female islets in response to T1D-related stresses. We will generate and analyse large datasets to identify key stress response events in mouse and human donor islets. Results will be presented at scientific conferences. By understanding these mechanisms, we will likely identify therapeutic targets that can lead to future drug and cell therapies for T1D. A focus on sex differences is also key to ensuring appropriate research translation to a wider population. Finally, a fundamental understanding of sex differences in protein synthesis has implications for studies in other cells and organs, as all cells need to make protein.
Research Pillar: Biomedical Research
Uncovering the role of long non-coding RNA PAN3-AS1 in acute myeloid leukemia
In Canada, Acute Myeloid Leukemia (AML) presents a significant challenge, with only a 30% five-year survival rate and 30% of patients relapsing after treatment. While the genetic mutations in AML’s protein-coding genes are well identified and characterized, the impact of changes in non-coding genes, especially long non-coding RNAs (lncRNAs), remains largely unclear. Our research has identified a specific lncRNA, PAN3-AS1, as a critical factor in leukemia development, with its high expression linked to worse outcomes in AML patients. Our goal is to unravel the molecular functions of PAN3-AS1 in regulating gene expression in AML and to develop targeted therapies against it. We plan to use comprehensive multi-omics analyses to understand PAN3-AS1’s effects and apply innovative drug delivery techniques, such as antisense oligonucleotides (ASOs) and lipid nanoparticles (LNPs), to target PAN3-AS1 in human cells. This work aims to enhance our understanding of lncRNAs in cancer development and spearhead new, effective cancer treatments.
Structural and Functional Investigation of Neuronal Calcium Channel Modulation
Cells contain highly complex protein structures that allow signals to be relayed from the outside environment using signaling receptors to proteins inside of the cell. One mechanism involves assembling protein complexes across different cell layers linked by proteins such as junctophilins (JPH). JPH proteins are found in the brain and muscles and work by interacting with receptors on the outer layer while simultaneously interacting with proteins on inner cellular structures such as the endoplasmic reticulum (ER). Thus, JPH places the outer layer of the cell and the ER in proximity allowing for a direct exchange of signals. This is essential for muscle contraction and memory and is linked to human genetic diseases. However, the interaction sites between these JPH proteins and their effect on receptors, such as voltage-receptor channels (Cav2), remain elusive. Here, we want to use X-ray crystallography and electron microscopy to solve the protein structure of JPH and find how it interacts and regulates Ca¬v receptors. This work will provide insights into JPHs’ molecular structure, cellular function and role in genetic diseases. The JPH-Cav molecular complex will serve as a resource for future mechanistic studies and drug designs.
Triggered release of anti-cancer drugs using hybrid lipid nanoparticle technology
Drugs used in cancer treatment, unfortunately, also can harm healthy cells. We’re working on a better way to deliver these drugs directly to cancer cells, minimizing damage to healthy tissues. Imagine tiny particles, like microscopic delivery trucks, that carry cancer drugs. These particles are made from fats and can hold both a cancer-fighting drug, doxorubicin, and special iron particles. What’s unique about these tiny trucks is that they release their drug only when hit by a certain type of radio wave. This means we can target the drug right at the cancer cells, releasing it quickly and precisely. Our first goal is to make these special particles. Then, we’ll test if we can use radio waves to release the drug quickly in lab experiments. Lastly, we hope to show that this method works well in treating cancer in animal studies. Previously, our team has successfully translated scientific research into practical therapies, and we believe this might be yet another example of our achievement in advancing the efficacy of cancer therapy and safety.
Quantifying navigational impairments in preclinical Alzheimer’s disease
Our brain contains a ‘cognitive map’ of the external world that helps us navigate, and encode/retrieve memories. Dementias such as Alzheimer’s Disease (AD) degenerate these regions, causing well-known memory impairments and much less well-understood navigational impairments. My research program seeks to quantify how navigation is impacted in early AD in rodents and humans.
Young and older human participants will navigate a virtual reality maze. We will quantify how their errors in positioning and navigating scale when the complexity of the task is increased. We will perform similar experiments in rats navigating a physical maze, where we can additionally record neural activity. We will then extend the task to participants diagnosed with preclinical AD, and rodent models of AD. We will characterize the behavioural and neural correlates of early progression of AD, with the goal of finding a metric that is predictive of AD-induced cognitive impairment, and its underlying neural mechanisms.
Over 60,000 British Columbians currently live with dementia. A non-invasive and affordable test such as this will allow clinicians to perform early diagnosis, and start approaches that reduce symptoms and improve quality of life.
Mucus-directed therapeutics to prevent and treat chronic microbiota-dependent diseases of the gut
The colon is teeming with life, not just due to our own cells, but also due to a rich and diverse community of microbes. Remarkably, this community is a virtual organ, helping to digest food and fight inflammation. Unfortunately, this “organ” can malfunction and cause chronic diseases like inflammatory bowel disease (IBD), which affects thousands of Canadians. How to promote the benefits and prevent the harmful activities of our microbiota is a central question. One major factor is gut mucus, a sugar-rich gel-like layer that surrounds the microbiota to act as a barrier to prevent their invasion. This mucus layer is defective in IBD. The objective of my research is to develop new ways to capture the protective power of human mucus to prevent and cure IBD. To do this I will use a new approach my lab developed to extract and purify human mucus to test its protective abilities in mouse models of IBD. We will also learn how microbes control mucus production so we can target these pathways in patients. Last we will use human colon cells to generate a “mucus factory” that can produce mucus with enhanced protective properties. The results of this research will illuminate new paths to restore healthy host-bacteria relationships in IBD.
Integrating functional glycomics and genomic screening to reveal new targets for cancer immunotherapy
All of the cells in our body are coated with a dense layer of sugar molecules. Cells in our immune system constantly “taste” these sugars. Some types of sugar taste good to our immune system, signaling that our cells are healthy. Other sugars (like those attached to invading bacteria, viruses or cancer cells) taste bad to our immune cells, triggering them to activate and try to protect us from disease. Sometimes, our own cells can become altered in ways that lead them to produce abnormal types of sugar molecules on their surface. When this happens, it can allow cancer cells to evade detection and destruction by the immune system. Our group applies powerful genomics technologies to better understand how human cells generate these immune-regulatory carbohydrates. This information allows us to predict when cell-surface sugars may become chemically altered and identify specific molecules that can be targeted for manipulating immune activity. The insights generated from our research directly impact the design of new immune-targeted cancer therapies.
Beyond Sex and gender: advancing a biosocial understanding of affective processes.
Affective processes such as stress and emotion are at the heart of how we understand ourselves and interact with the world around us. Human and animal research supports the role of sex and gender-related factors in affective processes; however, the neurobiological mechanisms that influence affective processing remain unknown. While sex and gender are traditionally defined, respectively and separately, as biological and social dimensions of a person, alternative approaches rooted in interdisciplinary research rather conceptualize our biologies as inseparable from our social experiences. The proposed program of research aims to explore how an interdisciplinary gender/sex approach (as opposed to the distinct gender and sex approach) influence the neurobehavioural processes of stress and emotion. This research will expand our understanding of how context shapes biological and subjective experiences of stress and emotion and advance the development of integrated theories that will shape the future of gender/sex research.
Evaluating microstructural changes in multiple sclerosis with magnetic resonance imaging
Multiple Sclerosis (MS) can be difficult to detect, diagnose, and treat. It is often initially assessed by excluding other potential disorders and diseases as well as (where possible) a confirmatory magnetic resonance imaging (MRI) exam. While MRI can confirm the presence of MS lesions in the brain, the exam is of limited use in explaining or predicting symptoms or prognosis.
Following the initial diagnosis, there are a number of medications that can be used to attempt delay the progression of the disease. However, it is challenging to assess the efficacy of a particular course of treatment unless disease progression is detected through the accumulation of additional disability or a follow-up MRI exam confirms the presence of new lesions.
There may be other changes to the brain which may help scientists and physicians to understand how and why MS progresses and identify how well medications are working for a particular individual. Thus, the objective of this work is to leverage the power of a safe, non-invasive, imaging tool (MRI) to detect and evaluation changes to the brain that can help us better treat patients with MS.
Errors, Uncertainties, and Ambiguities in Wearable Health Monitoring Systems
Healthcare and diagnostics have recently undergone a paradigm shift with a greater focus on remote health monitoring through wearable technologies. Advances in miniaturized electronics, wireless communications, and big data analytics are all converging in this space to take health monitoring out of the clinic and into the home. However, while the exponential increase in wearable technologies is driving excitement in this field, such technologies have found limited success in clinical integration. While consumers might find a plethora of smart gadgets from watches to rings that can track activity and heart rate, little of this information is getting utilized by clinicians. This is in part due to the lack of transparency and perceived inaccuracy of wearable monitoring systems. We will address this limitation by characterizing errors in measured real-world health signals, accounting for errors in user-device interactions, and capturing uncertainties and ambiguities in decisions that will allow wearable sensors and underlying machine learning algorithms to provide more contextual and nuanced information for clinicians. This will help clinicians decide when and how to apply wearable data to clinical decisions.