Research Location: University of British Columbia - Vancouver Campus

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.

Impaired arm and hand function after stroke (~85% of stroke survivors in Canada) is linked to altered brain activity and overactive brain areas. Practicing a task drives changes in brain areas important for function. Changes in these brain areas lead to recovery. But, overactive brain areas impede recovery. We can temporarily turn down overactive areas with brain stimulation to aid recovery. By targeting general brain areas important for movement, this non-invasive, painless approach shows promise. Yet, its response is varied. We think this is because overactive brain areas differ across individuals after stroke. We will target brain areas for stimulation on an individual basis to improve effectiveness – an approach not yet taken. The proposed work will 1) determine areas for stimulation after stroke by examining brain activity on an individual basis, and 2) pair individualized stimulation with task practice to aid recovery after stroke. We will show that improvements in hand and arm function are maximized when stimulation is tailored to the individual. This work represents a critical step in improving interventions for stroke recovery, leading to improved daily function and better quality of life for Canadians living with stroke.

Globally, persons living with HIV are aging, with women constituting over half of this group. Increasingly, women living with HIV (WLWH) are entering menopause, a crucial transition with impacts on overall health and well-being. Regrettably, there is limited research focused on how WLWH experience menopause, leading to a major gap in their quality of care. Preliminary studies suggest that WLWH may experience menopause with heightened symptoms. However, uncovering the true extent of this important relationship awaits detailed clinical analysis. Therefore, we undertake an interconnected set of aims to better understand the progression of menopausal symptoms within two Canadian cohorts of WLWH. For the first time, we evaluate how symptom severity progresses during the menopausal transition in this group. Subsequently, we assess whether hormonal imbalance underlies the increased severity of symptoms experienced in menopausal WLWH. Finally, we evaluate the clinical use of hormone therapy to treat these women which we predict is under prescribed for WLWH. By uncovering unique aspects of menopausal management in HIV, this work will enable development of tailored approaches to improve care for this vulnerable population.

Synovial sarcoma (SS) is the most common soft-tissue cancer among young adults. It is an aggressive tumor type in great need of new treatment options. SS tumors are defined by a specific genetic change that causes two separate genes to fuse into one. This new fusion-gene produces the SS18-SSX protein which is thought to remodel the cells epigenome, resulting in the activation and inactivation of a large number of genes. As SS18-SSX cannot be inhibited by any known drugs, we aim to identify the genes and regulatory elements that are directly affected by the protein. We have developed a novel SS mouse model and collected a large series of human tumors in order to study the effects of SS18-SSX in the context most relevant to patient. We will then use state-of-the art approaches to identify and disrupt the most important changes caused by SS18-SSX with the goal of identifying new treatment options for patients with this deadly disease.