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.
Program: Trainee
Accelerating the implementation of blood-based genomic testing for people living with metastatic prostate cancer in British Columbia
Prostate cancer is expected to be the most commonly diagnosed cancer in British Columbia (BC) by 2030. Modern patient management requires cancer genetic testing in order to understand cancer prognosis, choose effective treatments, and inform on cancer risk for patient family members. However, prostate cancer genetic testing is underused in routine care due to difficulties in obtaining representative and high-quality tumour material. In addition, we do not yet know which genes are the most important to test. Our existing tests in BC also do not cover all possible genetic changes, so clinically-meaningful results may be missed.
This research will optimize and apply a comprehensive genetic test in over 3000 people with advanced prostate cancer, predominantly from BC. To make an accessible and practical test, we will use patient blood samples and will use new technology to analyze the tumour DNA that cancers shed into the blood. Results of this study will tell us about the frequency and clinical importance of specific genetic changes in the BC population, and demonstrate feasibility of routine blood-based testing. Results will be translated to next-generation clinical-grade tests offered to BC patients going forward.
Advancing Orthopaedics Diagnostic Intelligence: Deep Learning and Generative AI models for Fracture Identification and Dialogue-driven documentation and Decision Making
Accurate radiographic assessment is essential in diagnosing pediatric fractures to prevent misdiagnosis. Pediatric skeleton anatomy exhibits both uniqueness and age-related variability, which enhance the challenges in correct radiograph analysis and diagnostic decisions. Therefore, we propose artificial Intelligence models for radiograph annotation and fracture identification using deep learning and natural language processing to analyze radiographs for fracture detection. Secondly, physicians may overlook crucial questions to pose during the doctor-patient dialogue, which may lead to misdiagnosis and incorrect decision-making. Therefore, we aim to equip the system with Generative Pre-trained Transformer (GPT) models to extract information from the dialogue. Our system extracts the important information, identifies missing information, and auto-documents the extracted information. We will develop a user-friendly software “Ortho-Assistant” with functionalities of automatic radiograph assessment, automatic clinical documentation, and assistance in diagnosis and treatment decision-making. In KT activities, we will publish the outcomes in reputable journals, present at conferences and workshops, and train the undergraduate students.
Understanding the health and social harms of drug re-criminalization within the context of homelessness
Drug criminalization is associated with a range of poor health outcomes, such as overdose. Without access to adequate housing, people who use drugs (PWUD) experiencing homelessness are more likely to use drugs in public, and thus are among the most impacted by criminalization. Recent changes to BC’s decriminalization policy re-criminalizing drug use in most public spaces (e.g., parks, sidewalks in front of buildings) will likely have significant implications for the health and wellbeing of unhoused PWUD. This study will examine how emerging re-criminalization impacts health outcomes, including overdose, for unhoused PWUD, and will develop novel approaches to community-based research in rapidly changing policy contexts. Research activities include interviews with unhoused PWUD and outreach service providers, observation in community settings, and analysis of text sources (e.g., policy guidance, press releases) to fully understand topic scope. By understanding the dynamic relationship between drug re-criminalization and overdose vulnerability for people experiencing homelessness, this research will generate ideas to guide future drug policy in BC, and that are scalable and adaptable to other settings pursuing drug policy reform.
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.
Sensorimotor interactions between the lower limb and pelvic floor: neuroplasticity and implications for management of urinary dysfunction after spinal cord injury
People with spinal cord injury (SCI) often experience problems with their bladder function, resulting in symptoms like urine leakage. The bladder and its associated structures are controlled by neural circuits located in the lower part of the spinal cord. This area also contains neural circuits that help control leg movements and sensation. Studies in animals showed that sensory input from the legs can affect muscles controlling urinary function. There is also evidence for such connections between these two systems in humans. For example, gait rehabilitation and electrical stimulation of nerves in the lower leg may help with bladder symptoms in people with neural injury. The reasons for these effects are unclear. However, our recent studies indicate that the pelvic floor muscles, which are crucial for maintaining continence, are activated when people with SCI walk with the help of an exoskeleton. To better understand these phenomena, this proposal will examine how sensory input from the leg affects pelvic floor muscle activity in able-bodied individuals and people with SCI, as well as the potential of using this neural connection to develop rehabilitation-based approaches to manage urinary dysfunction after SCI.
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.
Mapping the musical brain in dementia
Music is an important part of life for individuals with dementia and their loved ones. Numerous clinical studies have detailed music’s positive effects on quality of life in dementia care, however, much is still unknown about how music is processed in the brain, and how the brain adapts to neurodegeneration in dementia to maintain a connection to music. This is an important unanswered question as many assessment tools do not allow us to look at brain activity with persons with dementia in a way that is enjoyable and accessible to the individual. This project will record brain data during music listening and analyze the resulting brain network data for age- and diagnosis-related patterns. Music helps stimulate memories and promotes social interaction with loved ones, making it a beneficial addition to the lives of individuals with dementia. However, much still needs to be discovered about how and why music works. This study will provide information that can help improve access to music-based therapies for individuals with dementia in BC and will give researchers a greater understanding of brain adaptation in dementia.
3D bioprinting patient-derived neural tissues for screening potential treatments for Alzheimer’s disease.
Alzheimer’s disease (AD) is the most common form of dementia and continues to affect more people globally due to the aging population. AD currently has no treatment or prevention options aside from symptom alleviation, making it a high priority in medical research. Despite years of research, no AD treatments have been discovered since most studies have used tissue replicas (or models) that do not accurately act like the brain. This has led to presumed success of treatments in research, but failure in clinical testing in animal models. The use of three-dimensional (3D) models that contain brain cells organized in a more accurate 3D structure will allow for a better understanding of AD, which is the focus of this work. In addition, these 3D models can include patient cells to provide specific treatment options for those with AD. The patient-specific AD models will be used to test various drugs, including those with current approval for other diseases. The proposed research will provide new insight into AD treatments by using more accurate AD models to better understand this complex disease in research. The 3D tissue models will allow for better screening of treatment options, ultimately bringing us closer to finding a cure for AD.