During the development of Type 2 diabetes, the body often makes more of the blood sugar-lowering hormone insulin than normal. Recent research suggests excess insulin may cause weight gain and insensitivity to insulin. Studies from our lab showed that preventing this increase of insulin can reduce weight gain and extends lifespan in mice. Too much sugar consumption also contributes to obesity and diabetes, but how this happens is still unclear. Therefore, we aim to find out whether reducing insulin can prevent the detrimental effects of high sucrose and identify the underlying causes of obesity and diabetes. So far, our experiments with mice who were given sucrose drink in place of water, have revealed that mice given that have been genetically modified to produce less insulin are protected from higher body weight and blood sugar levels. With funding from Health Research BC, we will analyze the liver, muscle, and fat of these mice using powerful techniques that can profile thousands of genes and proteins in these tissues, rather than just a few at a time. These analyses will reveal the detailed changes in the cells in response to sucrose and insulin, which will tell us how they cause obesity and diabetes and help us develop strategies for preventing diabetes.
Research Pillar: Biomedical Research
Predictive biomarkers for ovarian cancer treatment: Analysis of patient of derived xenografts under treatment at single cell resolution
Each year in Canada, around 3,000 women will be diagnosed with high grade serous ovarian cancer (HGSOC) — the most common type of ovarian cancer. Despite good responses to first line treatments for many women, it comes back as a resistant disease. Targeted treatments such as PARP inhibitors (PARPi) have made a big difference to HGSOC that is deficient in a DNA repair pathway (Homologous recombination repair), but this only benefits around 50 percent of women with HGSOC. PARPi combinations with drugs that target angiogenesis and the immune response remain under investigation. This project will investigate how chemotherapy vs. targeted therapies differentially affects the DNA damage and immune response in cancer and how effective non-chemotherapy combination treatments work, including different doses and schedules. Also, which patient might benefit from which treatment and when for example should the targeted therapies be given before or after the chemotherapy? Creating models similar to humans, we will transplant patient tumors (removed at surgery) on the skin and inside the abdomen of mice and analyze the molecular nature (at single cell level) of these tumors before/after treatment. Results of these studies will inform future clinical trials.
Air pollution as a modulator of molecular, structural, and clinical outcomes in patients with fibrotic interstitial lung disease
Interstitial lung diseases (ILDs) are serious conditions resulting in lung scarring, breathing difficulties, and a severely shortened lifespan. Air pollution is associated with ILD development and progression, but we do not understand why. This project aims to answer this question by looking at cellular and genetic changes that occur in the lungs of patients with ILD following exposure to air pollution. Using satellite-derived air pollution and clinical data from patients, we will determine if certain genes result in worse clinical outcomes when patients with ILD are exposed to more air pollution. Next, we will examine how air pollution modifies how genes are turned on or off in ILDs, through a process called DNA methylation. Lastly, we will use high-resolution imaging tools to understand how the structure of the lungs change in response to air pollution in patients with ILD. This research will help us to understand how air pollution contributes to progressive lung scarring in patients with ILD and may identify new targets for therapies to reverse lung scarring. This work will inform environmental health policies aimed at protecting vulnerable populations, including patients with ILD and other chronic lung diseases.
Cholesteryl ester transfer protein-mediated regulation of HDL cholesterol levels and clinical outcomes in sepsis
Sepsis is the overwhelming immune system response that occurs when someone develops a serious infection, and is responsible for one-fifth of all deaths worldwide. Sepsis occurs when the immune system becomes over-activated by lipid components present in bacteria, and ultimately leads to dysfunction of critical organs and death. These bacterial lipids (called pathogen-associated lipids or ‘PALs’) are transported through the bloodstream by lipoproteins, the same “vehicles” that are used for cholesterol transport. Among these vehicles, high density lipoprotein (HDL) plays a central role transporting PALs. However, HDL levels significantly decrease during sepsis, leading to reduced clearance of PALs. In our previous work, we discovered that inhibiting a specific gene called cholesteryl ester transfer protein or CETP preserved HDL levels during sepsis, suggesting that this may be a new approach to treat sepsis. We now aim to study the mechanism by which CETP regulates HDL to combat bacteria, and whether CETP inhibition will improve mouse survival in a clinically-relevant sepsis model. Completion of this project will provide new insights into the therapeutic role of CETP inhibitor in sepsis, ultimately improving the health of Canadians.
Cryo-EM studies of activators and inhibitors of KCNQ1 and KCNQ1:KCNE1 channel complexes
Type 1 Long QT syndrome (LQT1) and Short QT syndrome (SQT) result in life-threatening irregular heartbeats that can cause sudden death. LQT1 affects around 1 in 2,500 adults, whereas SQT may impact twice as many individuals, with high prevalence of congenital LQT in a First Nations community in Northern BC. Current treatments are inefficient and therefore, new therapeutic strategies are needed. Abnormalities of the protein, KCNQ1, result in these diseases. Normal KCNQ1 function moves charged ions through heart membranes. We generally know how KCNQ1 functions in health and disease; however, the exact mechanisms are not yet fully understood. We need to study the 3D structural changes that happen to KCNQ1 in the presence of certain compounds to understand how KCNQ1 functions. I will study the 3D structures of such complexes by using cryo-electron microscopy, a technique to study structural biology, and functional characterization. The new knowledge that will be produced will help better understand how such proteins cause disease and lead to new therapeutics for better human health.
Fibrinogen promotes a microglial-mediated inflammatory response following adolescent repetitive mild traumatic brain injury
Concussions are a major health issue in Canada. Adolescents are an at-risk population for concussions because they are in an age range that is often engaged in contact sports and high-risk activities. Microglia, the brain’s resident immune cells, respond to these injuries, causing an inflammatory response. Concussions can damage brain blood vessels, promoting the release of fibrinogen, a protein not present in the healthy brain. Fibrinogen interacts with microglia, promoting an inflammatory profile that can alter neuronal functioning, leading to behavioural deficits. This project will block fibrinogen’s interaction with microglia using an ecologically valid rodent model of concussion. We will assess short- and long-term memory with well-known behavioural tests. In addition, we will assess microglial activation and type using immunohistochemistry, and assessing neuronal connectivity using field electrophysiology. Adolescence is a period of significant development marked by rapid learning and substantial brain growth/maturation. As such, expanding and fully characterizing changes in brain circuitry mediated by fibrinogen/microglia interactions following concussion may provide avenues for preventative and therapeutic interventions.
Outcomes of a ketogenic dietary intervention on the gut microbiome-microglial brain axis and schizophrenia-like behaviour in mice exposed to a double-hit immune challenge
Alterations in microorganisms present in the gut are associated with various mental health disorders. It is possible that this is due to changes in microglia, the immune cells that fight infections in the brain. Microglia can consume neurons, which are the cells that talk to one another in the brain. It is possible that changes in gut microorganisms make these immune cells to eat up brain cells excessively and uncontrollably, which causes mental illness. To understand this, we will infect laboratory mice with infectious agents during pregnancy and expose them to stress during adolescence. After testing the mice for behavioral alterations, we will use imaging techniques to assess how gut microorganisms can influence microglia. We will then determine if ketogenic treatments with a clinically approved high fat and low carbohydrate diet, showing benefits on the gut and brain, can reverse harmful effects on these immune cells in the brain. Together these investigations will provide novel insights into how the gut microorganisms can affect the brain immune cells and alter behavior, resulting in mental illnesses. This research may provide new targets for the therapeutic management of mental health conditions that include schizophrenia.
Regulation of anabolic metabolism in anti-tumour T cells
Our immune system protects of our body by detecting and destroying cells that are potentially cancerous. Sometimes, our immune system fails to detect a problem, leading to cancer. In pediatric cancer, CD8 T cells fail to destroy cancer cells. CD8 T cells are white blood cells specialized in the detection and attack of cancer cells. Like us, CD8 T cells need to “eat” to stay alive, to move, and to function. Without nutrients, they can’t fight off cancerous cells. In cancer, there is a fight for nutrients between CD8 T cells and cancer cells. CD8 T cells have to quickly adapt to make sure they can maintain their protective functions. We know that CD8 T cells can rapidly switch from using nutrients to grow, to burning them to make energy, but we do not know how it is regulated. The aim of my project is to study how CD8 T cells know which nutrients are around them, and how they “choose” to switch between growing and burning. Why is it important? If we grow CD8 T cells in a laboratory setting, restrict their food, and re-feed them, they provide better protection against cancer. Understanding how CD8 T cells “eat” and use nutrients to grow or burn energy to kill cancer cells will help develop better therapies to treat pediatric cancer.
Sex specific characterization of microRNAs in fibroadipogenic progenitors in cancer cachexia
More than 80 percent of patients with cancer encounter a severe loss of muscle and fat leading to a devastating condition called cachexia, a condition that severely affects the quality of life. Incidence of cachexia is higher in males than in females. In general, and in cancer, men have increased muscle mass while women have higher fat mass. Understanding the inherent sex-differences in disease will aid in developing effective treatment options. During muscle injury, different types of cells in muscle act in synchrony for its repair. One type of supporting cell is called as fibroadipogenic progenitors (FAPs), which provide the required growth factors for muscle regeneration. Impairment in FAPs production or function would lead to unhealthy accumulation of fat in muscle, leading to muscle wasting. The role of molecules such as microRNAs (miRNAs) contributing to this impairment remains unknown in cachexia. miRNAs are small molecules that controls expression of several genes. The current proposal aims to understand the role of sex-specific dysregulated miRNAs in FAPs and if therapeutically targeting the defective miRNAs may ameliorate muscle wasting thereby improving survival, quality of life in patients with cachexia.
Medulloblastoma plasma membrane proteomics to inform optimal immunotherapy design
Brain cancer is the most common pediatric solid cancer, devastating the lives of more than 5,000 children and their families every year in North America. Current chemoradiotherapy approaches are often ineffective and cause serious side effects on the developing brain, such as permanent seizures and learning disabilities. Thus, more effective and less damaging therapies are urgently needed. Immunotherapy has been recently credentialed as a breakthrough in cancer therapy, with novel immunotherapy agents approved by the FDA for the treatment of childhood cancer. There is every indication that this progress presents the tip of the iceberg and that with continued efforts, effective immunotherapies can be developed for many currently incurable pediatric cancers. The ability for cancers to grow rapidly is in part due to the activation of specific proteins exposed on the membrane of cancer cells. The goal of immunotherapy is to target cells exposing these proteins while sparing normal, healthy cells; however, a major barrier is that most proteins on the surface of medulloblastoma cells are currently unknown. In this proposal we will identify optimal targets to ultimately develop immunotherapies against medulloblastoma.