Acute kidney injury (AKI) complicating critical illness is an important problem, contributing to roughly 1.7 million deaths worldwide per year. Treatment is limited to dialysis, which is costly and frequently unavailable. Preventing AKI is a critical step to reduce deaths. Acetaminophen (Tylenol) has the potential to reduce AKI caused by oxidative damage from hemoglobin (released from red blood cells) and myoglobin (released from muscle cells). Acetaminophen inhibits this oxidative damage and reduces kidney dysfunction in animal models, and in patients after cardiac surgery or in patients with sepsis.
I previously led a trial in adults with severe malaria showing that acetaminophen improved kidney function and reduced the odds of developing AKI. Since children bear the major burden of malaria, it is crucial to test this protective effect in African children where 45% of patients have AKI. The goal is to assess the role of acetaminophen as a kidney protective therapy in severe malaria.
I will conduct a randomized controlled trial of adjunctive acetaminophen in African children with severe malaria. If the trial is positive, the results would change severe malaria management globally. It could be rapidly scalable as acetaminophen is inexpensive, safe and widely used. These findings will have broad implications for other major causes of hemoprotein-mediated AKI including crush injury and sepsis, which directly impact thousands of Canadians.
Deaths due to opioid overdoses have reached epidemic proportions in Canada, with nearly 8,000 Canadians losing their lives in the last two years. Knowledge of how rescuers can best respond to cardiac arrests due to opioid overdose is urgently needed.
Unfortunately, there is a paucity of studies examining opioid-related cardiac arrest; therefore, there is a lack of evidence to guide bystanders or professional rescuers on how best to intervene. Specifically, there is controversy regarding the benefit of bystander-initiated rescue breaths and paramedic-delivered naloxone. The goal of this project is to determine best resuscitative strategies for opioid-related cardiac arrest to inform national and international guidelines.
In this project I will create the largest and most comprehensive dataset of cardiac arrest cases due to opioid overdose in the world, complete with detailed data on bystander and professional interventions, and patient-oriented outcomes. I will analyze this data to determine the best treatment strategies. In addition, I will examine the benefit of public access opioid overdose kits and their optimal locations. I will implement a knowledge translation and dissemination plan in collaboration with key knowledge-users.
Many patients with depression struggle to return to their full level of functioning in work and other areas of life. These poor functional outcomes in depression may be related to cognitive difficulties, as patients demonstrate problems with memory, attention, and problem solving. We however lack treatments for these difficulties. Cognitive training, consisting of tasks to target cognitive deficits, has been tested but shows inconsistent results in depression.
Virtual reality (VR) – which is immersive, interactive and can recreate real world settings – may enhance cognitive training. VR cognitive training has shown benefits in stroke and schizophrenia. However, a full course of VR cognitive training has not been tested in depression.
With the National Research Council Canada, we have designed a VR cognitive training suite, the 'bWell' Cognitive Care Platform for Depression. We plan to pilot bWell in patients. This will determine if bWell is feasible, and will allow us to gather patient feedback to improve the tasks. We will then proceed to a clinical trial comparing bWell to standard cognitive training in depression. Our goal is to determine if VR can improve cognitive and functional outcomes in depression.
Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen often responsible for hospital-acquired infections, which can be very difficult to treat due to antibiotic resistance. A common mechanism of resistance is the expression of beta-lactamase enzymes, which break down and disarm classical beta-lactam antibiotics, such as penicillins. Beta-lactam antibiotics act by breaking down the bacterial cell wall, producing cell wall fragments that induce expression of the beta-lactamase, AmpC. In many Gram-negative bacteria, AmpC base expression is low but can be induced by exposure to beta-lactams. Current beta-lactamase inhibitors are ineffective against AmpC, therefore blocking upregulation is a potential strategy to combat the resistance effects. AmpG, a transporter that imports the cell wall fragments needed for AmpC expression, is an exciting new target. This project aims to solve the first atomic resolution structure of AmpG and further our understanding of how the transporter functions. This project has the potential to translate directly into the development of new AmpG inhibitors and treatment strategies that preserve the effectiveness of current antibiotic therapeutics in the clinic and community.
Campylobacteriosis is an infectious diarrheal disease and one of the largest contributors to hospitalizations and deaths from food poisoning in Canada and worldwide. It is usually caused by consumption of food or water contaminated by the bacterium Campylobacter jejuni, resulting in watery or bloody diarrhea, fever, and serious post-infectious illnesses. This illness is especially dangerous for very young or old people, made worse by lack of a vaccine and increasing frequency of infections that are resistant to treatment by current antibiotics. A recent WHO report identified C. jejuni as a pathogen with a 'high priority for research and development of new antibiotics'. To thrive and cause campylobacteriosis, C. jejuni must take up nutrients such as iron, which is present in the human gut.
This project will investigate the structural components of a newly-identified system which helps this bacterium collect iron from its surroundings during infection. Better understanding these structures could allow us to develop new antibacterial agents which fight infection by preventing the bacterium from collecting iron. These outcomes could be extended to several other disease-causing bacteria which contain related iron-collecting systems.
Thousands of Canadians receive bone marrow transplants each year to treat cancer and immune disease. Unfortunately, not only is this treatment dangerous, it is only effective for a small subset of cancers and immune disorders. Our goal is to provide a safer alternative to marrow transplantation that can be applied to a broad set of indications.
A bone marrow transplant provides a patient with stem cells that will ultimately produce new immune cells capable of remedying disease. These transplants are dangerous because the recipient needs to undergo toxic chemotherapy or radiation to make room in their marrow for the donor's stem cells. To avoid this risk, the Zandstra lab has pioneered a method of producing immune cells from stem cells in the laboratory. Unlike blood stem cells, immune cells can be transplanted without destroying a patient's existing marrow.
To make this approach even more useful, I will genetically modify stem cells in the lab to correct disease-causing mutations and improve their cancer-fighting properties before turning them into immune cells. By providing a renewable supply of immune cells tailored to safely fight disease, we aim to reduce the sizeable impact of cancer and immune disorders in the province.
Insulin is a hormone that is crucial for maintaining normal blood sugar levels and is produced by beta-cells in the pancreas. If the amount of beta-cells is insufficient, or beta-cells stop making insulin, blood sugar levels start to rise which can lead to diabetes. Islet transplantation can supply the necessary amount of beta-cells and achieve superior glucose control over exogenous insulin injection, but is extremely limited by its reliance on organ donations. As a result, only a small fraction of people afflicted with diabetes currently benefit from these cell replacement therapies.
Our project aims to direct pluripotent stem cells to develop into fully mature, functional human islets in vitro. The stem cell-derived islets have similar size, endocrine cell composition and functionality as primary human islets and can provide an unlimited source of islet donors, permitting widespread application of islet-cell replacement therapy to treat diabetes. Moreover, stem cell-derived islets can also be suitable models for drug screening, regenerative medicine development and understanding the pathogenesis of diabetes.
Participation in regular physical activity is associated with reduced risks of cardiovascular disease, overweight/obesity, type 2 diabetes mellitus, numerous cancers, mental and reproductive health problems, and osteoporosis. Yet, only 9% of Canadian children and adolescents and 20% of Canadian adults meet physical activity guidelines. An essential component of being active involves having the skills needed to successfully participate in an activity. Skill development across time should be viewed in the context of how it leads to skillful performance and in terms of how movement skills support and maintain a lifetime of physical activity.
However, skill development across time is not well understood in relation to
- how competent adults within the general population are at various movement skills and
- how the association between movement skills and activity changes across the lifespan. To address this shortcoming, cohorts of 25 males and 25 females in 10-year increment age brackets between 5 and 75 years will be recruited for participation in this study (N = 350). Measures of motor skill competence, physical activity and enjoyment will be assessed.
Key outcomes will include:
- movement skill development trajectories across the lifespan
- determination of the strength of association between movement skills and health-enhancing physical activity across the lifespan and
- determination of the mediating effect of enjoyment on physical activity participation
Skeletal and heart muscle contraction requires calcium ions. Calcium ions enter muscle cells through 'calcium channels', which are effectively gates comprised of protein. The exact timing of the opening and closing of these gates is critical for normal muscle function, whether in maintaining a regular heartbeat or in enabling physical movement of the body as a whole. Any deviation in these calcium channels can cause calcium excess, which may result in disease. These include inherited cardiac arrhythmias or muscular disorders (e.g. Native American myopathy).
This project aims to uncover how other, ancillary proteins called 'STACs' can interact with these gates to promote their opening and how these STACs might contribute to diseases of dysregulation.
The lack of effective antibiotics in cases such as surgeries, transplantations, early-term and complicated births, sepsis etc. could merely lead to death as antibiotics are crucially needed for treatment. Sepsis for instance, annually kills ~8 million people worldwide with almost 40% of all deaths are linked to antibiotic failure. Likewise, infections caused by bacterial biofilms represent ~65% of all clinical diseases, and there are no antibiotics to treat bacterial biofilms, specifically. Here, we propose using new synthetic and biosynthetic technologies to develop novel molecules alternative to antibiotics, particularly antimicrobial peptide-like compounds, to address a wide range of hard-to-treat bacterial infections.
Starting from our previously developed immunomodulatory and antibiofilm peptides, we aim to explore the structure-activity relationships of those peptides and biosynthetically design stable and highly active mimetics. We plan to use advanced animal models, synthetic and isolated human tissues (skin and lung tissues) for testing and addressing preclinical issues such as stabilities, formulations, toxicities, and optimal therapeutic dosing. If successful the proposed study will provide the first novel therapeutic strategy to tackle bacterial infections and these newly developed compounds would have a significant impact in treating diseases and preventing deaths.
