Program: Trainee

Nontuberculous mycobacteria (NTM) are a group of environmental bacteria, commonly found in the water and soil. Many species of NTM – such as Mycobacterium avium complex – can cause chronic lung infections, which are difficult to treat and often associated with progressive lung damage. The number of people affected by NTM lung disease has been increasing around the world, however, we do not have a good understanding of its local impact. In this project, we will use province-wide data to characterize the scope of NTM lung disease in British Columbia (BC) and examine treatment patterns. We will also assess challenges associated with treatment, including early treatment discontinuation and bacterial resistance to antibiotics. Findings from this study will improve our understanding of the patient population affected by NTM lung disease in BC and inform efforts to improve the care of these patients.

With current treatment options patients with Osteosarcoma have a 5-year survival rate of about 76%, but for 3 out of 4 patients diagnosed with Osteosarcoma that has spread beyond the primary site will not live 5 years passed their diagnosis. There is clearly an unmet clinical need to develop new options for these patients. Immunotherapy aims to notify your body of the malignant cells and target them for destruction by the patient’s own immune system, however, its success in pediatric cancers is still lacking. One crucial aspect of developing successful immunotherapies is having a good target, and these are often targets that sit on the outside surface of the cancer cells. Our team has already characterized this area in Osteosarcoma and found a protein, TMEM119, to be extremely specific to Osteosarcoma. We have demonstrated that TMEM119 is not expressed in normal tissues, only in some sarcomas, making it an ideal strategy to target, but more work is needed. With this project, we aim to understand the role of TMEM119 in Osteosarcoma by selectively switching it off and examining whether this can prevent the spread of Osteosarcoma. We hope that our work can contribute to the development of a new strategy for Osteosarcoma patients.

Microglia are the immune defense cells located within the brain and also play a big role in the maintenance of a healthy brain by scavenging and removal of damaged/unnecessary neurons and synapses. This “synaptic pruning” function is important for the proper developmental wiring of the brain. Huntington’s disease is a disorder of the brain, which gets worse over time. It is caused by DNA repeat expansions in Huntingtin gene leading to neuron cell toxicity and death. Of late, the role of microglia in Huntington disease development has been gaining momentum. I plan to study the effects that different DNA repeat sizes in Huntingtin gene have on the disease progression, through the repeats’ influence on the microglia’s behaviour and function as well as on the neurons’ reaction to synaptic pruning. Further, I will check if correcting either microglia/neurons or both would be useful in reducing the cellular symptoms of Huntington’s. The results will throw light on early development changes (influenced by different sizes of DNA repeats) that would occur in Huntington’s disease and also reveal how they impact a disease like Huntington’s, which usually affects patients late in their life.

In human cells, DNA is folded such that distant points on the linear genome may lie close together in 3D space. This allows interactions between some regions of DNA while separating others, thus dictating the connections between genes and regulatory elements, and exerting control over gene activity. When 3D genome organization is disrupted, the wiring of genes and regulatory elements can be altered and lead to aberrant interactions that inappropriately activate pro-cancer programs.

Viral infections cause 10% of cancers, of which 50% are attributable to human papillomaviruses (HPV). Cervical cancer is an HPV-driven disease, and in over 80% of cases, viral DNA becomes inserted (“integrated”) into the DNA of infected cells, leading to genome disruption. I will profile DNA folding in cervical cancer cells to investigate how HPV integration disrupts the organization and regulation of the host genome, and how this dysregulation contributes to cancer.

My study will contribute to understanding the role of HPV integration in cervical cancer. Findings in this context may improve our understanding of genome dysregulation in other HPV-associated cancers, and provide general insights into how viral integration can promote cancer progression.

This project aims to understand the basic function of the skeletal muscle, and how mistakes in this function can lead to life-threatening disease. A key element of the complex biochemical process known as muscle contraction is a specific particle, named calcium ion. Both the heart and skeletal muscle tissues rely on the movement of calcium ions within each individual muscle cell. This movement occurs through specialized proteins that form ‘pathways’ or ‘channels’. When this pathway doesn’t work properly, however, there can be deadly consequences. In the heart, for example, mutations in the DNA can lead to faulty channel proteins that can no longer allow the normal passage of the calcium ions. This leads to heart rhythm disorders that can result in sudden cardiac death. How exactly the mutations cause this is not fully understood. We aim to understand this, by looking at the detailed 3-dimensional structure of the pathway, and by comparing healthy proteins with diseased versions. Because proteins are too small to see with the naked eye or even with very good light microscopes, we need to use a special tool. We will make use of a so-called ‘electron microscope’, whereby the protein is bombarded with electrons instead of light.

The makeup of bacterial communities in the gut is strongly linked with inflammatory bowel disease (IBD) including Crohn’s disease and ulcerative colitis. Pathobionts like E. coli are opportunistic pathogens that exacerbate gut inflammation in IBD but respond poorly to antibiotics. Bacteriophages (phages) – highly specific bacterial viruses – can alter gut microbiome composition, and so could be used in IBD treatments. Phages, however, undergo evolution – they change over time in response to their environment. Their safe and effective use in treatments therefore requires an understanding of how they co-evolve with the pathobionts in the gut. Here, I will study E. coli pathobiont and phage co-evolution in the gut in response to malabsorption – a key symptom of IBD that causes high gut osmolality (concentration of molecules). Bacteria can adapt to these changes by regulating osmotic channels, but at a cost: phages use those channels to infect. By combining a computational model of bacteria-phage growth with evolution experiments performed in the gut, I will determine the role played by malabsorption in driving bacteria-phage co-evolution and reducing pathobiont load, in turn informing the development of phage therapies for IBD.

Obesity and type 2 diabetes are significant public health issues, with 31% of British Colombians living with prediabetes or diabetes. Not participating in regular physical activity increases the risk for obesity and type 2 diabetes but we still don’t know exactly how. Within days of switching from high activity to inactivity, people have an increase in the blood sugar lowering hormone insulin but at the same time become resistant to insulin’s action. This is followed by weight gain.

Recent research has found that high insulin levels can cause insulin resistance and weight gain. It is possible, then, that the increased insulin level seen when becoming physically inactive causes insulin resistance and weight gain, increasing the risk of obesity and type 2 diabetes. Our study will test this hypothesis directly by using genetically modified mice that make less insulin. These mice will perform high physical activity on running wheels and then transition to low physical activity when the wheel is locked.

By having a greater understanding on the mechanisms behind physical inactivity increasing the risk of obesity and type 2 diabetes, our findings could help develop treatments to prevent the onset of these diseases.

Organ transplantation is a lifesaving therapy. In 2021, in Canada around 2,782 organ transplants were performed. Key to success in organ transplantation is to suppress the immune system and prevent rejection. Current treatment using immunosuppressive drugs have reduced the incidents of rejection, however, such global immunosuppression leads to severe side effects. Thus, new approaches are needed for improved graft survival. Graft rejection is a comprehensive immune reaction initiated due to the damage of blood vessel lining (glycocalyx) during organ procurement and preservation. Such damage mediates the migration of a variety of immune cells post-transplantation, and worsen overtime triggering rejection. In this project, we will rebuild native immune-deactivating activity using immunosuppressive polymer conjugates via a novel organ engineering approach to prevent such damage and graft rejection. We will study the mechanism of this approach and apply it in the transplantation of arteries and kidneys as proof-of-concept. This new organ engineering will reduce the post-transplantation treatment costs, improve patients’ quality of life and may lead to transplantation without immunosuppressive drugs.

The lack of effective treatment options for neurological disorders underlines the critical need to identify new drug targets. Neuroinflammation is one of the most common disease mechanisms in various neurological disorders, which makes it a promising target for novel therapies. One of the major barriers facing the development of effective therapies that improve function in individuals with neurological disorders, such as spinal cord injury and multiple sclerosis, is the lack of suitable biomarkers. To address this issue, we aim to develop “spinal cord thermometry” or SCT. SCT can be done in awake individuals using data acquired from a non-invasive MRI scan. SCT, we believe, may provide valuable information on the degree of inflammation ongoing in the injured spinal cord. This is, conceptually, very similar to how body temperature indicates if you have an infection. Our study will develop the necessary methods to measure SCT, first in healthy individuals, before application in individuals with spinal cord injury and multiple sclerosis. Our research will provide a novel biomarker of neuroinflammation in the spinal cord and help identify ways to treat diseases associated with neuroinflammation.

Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has caused 6.5 M deaths globally. Despite currently available vaccines and treatments, we need more effective therapeutics to combat the ongoing SARS-CoV-2 pandemic which remains a major global health and economic challenge.

RNAaemia (a high level of viral RNA in the blood) is a predictor of poor health outcomes in COVID-19. Therefore, the MOD-RNA pipeline was developed to analyze RNA produced by SARS-CoV-2, but in a manner consistent with the principle that RNA is the epicenter of genetic information. My research reveals SARS-CoV-2 produces small RNAs with an affinity for human genome enhancer regions. These findings support that SARS-CoV-2 has evolved epigenetic interference to promote viral propagation by abrogating transcriptional networks critical to the infection process.

To facilitate ongoing surveillance of SARS-CoV-2 variants of concern, I plan to continue building out MOD-RNA as an open-access tool, which will also be broadly applicable to other current and emerging pathogens. This research and further development of MOD-RNA is critical to our fight against SARS-CoV-2 because of the potential to find new therapeutic opportunities against COVID-19.