Program: Trainee

New toxins for incorporation into treatments known as antibody-drug conjugates are urgently needed to ensure therapeutic action. These antibody-drug conjugates consist of an antibody, designed to target a specific group of cells, attached to an active drug that elicits a desired cell response. While most emergent payloads for clinical application target tubulin, making them redundant, the death cap mushroom contains a toxic peptide called alpha-amanitin with unique biological activity. Amanitin presents its toxicity by preventing the conversion of DNA to RNA, a process required for protein synthesis. This inhibition ultimately leads to cell death.  Amanitin’s high toxicity provides potential for a low dose cancer therapeutic if general toxicity to non-cancerous cells can be avoided. I seek to investigate the feasibility to harness amanitin’s bioactivity while delivering the toxin specifically to cancer cells by attaching a targeting agent. In order to facilitate these investigations, I will develop a scalable method to generate substantial amounts of the toxin. By utilizing this targeted approach, we anticipate a cancer cell-specific delivery of the toxin, which in turn would attenuate the off-target effects and general toxicity.

Transplantation is a cure for end stage organ failure, but a successful transplant requires a life-long use of immunosuppressive drugs to prevent organ rejection. The resulting lower immunity leaves patients in a complex medical condition because increases the risk for infections and cancer.

A specific type of immune cell, called regulatory T cells (Tregs), moderates the reactivity of the immune system and favours the transplanted organ acceptance. However, to maximize the use of Tregs as therapy, Tregs need to specifically recognize proteins on donor organs. A method to engineering Tregs to be specific to donor-organ is introducing a chimeric antigen receptor (CAR). However, currently available CARs may not work properly in Tregs and in a transplantation context.

This project aims to build this method by using different gene engineering strategies to maximize the success, safety and applicability of this technology in order to reduce the need of immunosuppressive drugs. The fine-tuning of Treg-based therapies for their use in transplantation could have important benefits to the health and life quality of persons with a transplanted organ, and could mean a huge advance in regenerative and personalized medicine.

Anxiety and depressive symptoms are the most common mental health problem in children born very preterm (24 – 32 weeks gestation).  Our previous work found pain-related stress of frequent daily procedures during hospitalization across a period of rapid brain development and programming of stress hormone (cortisol) expression to be associated with later anxiety/depressive symptoms. Longitudinal studies examining how this vulnerability develops across early childhood in this population are scant. In an internationally unique longitudinal cohort of children born very preterm, I will examine whether early pain-related stress and neonatal brain development interact with levels of cortisol across childhood, altering trajectories of anxiety and depressive symptoms, at ages 1.5, 3 and 4.5 years, differentially for boys and girls. Moreover, I will identify specific parent interactions that may reduce anxiety/depressive symptoms across development. By identifying parent interactions that improve child outcomes at multiple levels (brain, stress and behavior), my research will lead to development of inexpensive, practical ways for parents to help their children, benefitting families in B.C. and beyond.

Cytomegalovirus (CMV) is a virus that is present in 50-90% of adults globally, depending on the region. When a woman either becomes infected for the first time or reinfected during pregnancy, she may pass the infection to her fetus, which often causes hearing loss and intellectual disability in the child. CMV is the most common congenital infection worldwide. Women usually become (re)infected with CMV from virus shed by young children but a better understanding of how children transmit CMV to mothers is critical for designing strategies to prevent congenital CMV. 

We aim to determine how much shedding of the virus in saliva and urine of young children is required to transmit the infection to their mothers and what strains of virus successfully infect. To achieve this, we will collect samples from new mothers and their children for 1 year in Nairobi, Kenya, where rates of CMV infection are very high. Statistical testing will be used to evaluate risk factors for child and maternal (re)infection with CMV. 

This research project will provide invaluable information on CMV transmission and will inform the development of a vaccine to prevent maternal (re)infection and the resulting harm to children from congenital CMV infection.

One in eight Canadians suffers from osteoarthritis (OA), a debilitating joint disease that frequently includes bone bruises, known as BMLs. The question we want to answer is, do BMLs result from changes in muscle strength and coordination, or poor condition of ligaments (connecting tissues) or cartilage (smooth joint lining) that cause the cartilage loading to increase? This study investigates whether BMLs might be a result of the loading environment of the knee. Though the exact cause of these bruises is not known, they have been linked to increased pain and worsening of OA. This study will measure the size and location of BMLs in people with OA and relate them to cartilage contact and stress (loading over an area). A unique standing Magnetic Resonance Imaging Scanner (MRI; i.e., looking inside the body with powerful magnets in an upright position) will be used to image OA patients during a knee bend. The BMLs will be mapped over the contact areas and stresses. Findings will provide insights into what positions (e.g. depth of a knee bend) yield contact and stress closest to the BMLs. If BMLs are linked to loading, clinical changes can be made to loading (e.g., bracing) or drugs may be taken to intervene.

Osteoarthritis is a painful joint disease and leading cause of disability that affects over 6 million Canadians. The knee is one of the most commonly affected joints. Knee osteoarthritis (KOA) starts with mild joint pain and stiffness that worsens to extreme pain, often requiring surgery if left untreated.  Being able to identify people with KOA in primary care at an early stage of disease would help promote less invasive treatments. Yet, primary care clinicians report many barriers to identifying and treating KOA. The proposed study works with primary care clinicians and their electronic medical records to identify patients with KOA. I will examine the prevalence of KOA across Canada and learn about KOA risk factors like previous joint injury and obesity. As well, the management approach of primary care clinicians for KOA patients will be analyzed. Lastly, a secure online KOA dashboard will be pilot tested in a small group of primary care clinicians. This dashboard will combine the electronic medical record data with patient-selected patient reported outcome measures (PROM) on pain, symptoms, physical activity, and quality of life to inform primary care clinicians and guide their treatment for KOA patients.

Many neurodegenerative disorders are characterized by the accumulation of proteins forming toxic aggregates inside neurons. Certain proteins contain regions with repeated amino acids that can favor the aggregation process. In the cell, the molecular chaperone system maintains a fully operational protein environment by helping proteins reach and retain their final structure, prerequisite for their functionality. However, two chaperones (DNAJB6b and DNAJB8) were recently identified to also prevent protein aggregation and prolong the lifespan in Parkinson´s and Huntington’s disease mouse models, making them interesting potential therapeutic targets.

Our goal is to identify which proteins inside the cell require DNAJB6b and DNAJB8 for proper folding. We will identify the “client” proteins of the two chaperones by using protein mass spectrometry and biochemical methods. The validation of the newly found interactions, together with the determination of a pattern recognized by the chaperones, will allow the potential design of new therapies for the treatment of amyloid-based neurodegenerative diseases.