Research Pillar: Biomedical

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.

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.

As our population ages, an increasing number of Canadians experience difficulties with their vision. Although it is well known that both normal aging and age-related eye disease can affect a person's ability to see fine detail (such as in reading), tests of visual acuity used in regular eye examinations do not provide a complete picture of a person's ability to see in everyday situations, such as exercising and driving, where moving objects are often involved. Moreover, these tests often demand verbal instructions and do not accommodate sufficiently for the multilingual population of Canada with a range of cognitive functions. We propose to develop a technology utilizing eye movements to assess visual motion processing.

Our research will gather scientific evidence to understand the relationship between motion processing and eye movements in healthy seniors and patients with ophthalmic diseases, and whether it is practical to introduce the technology into clinical practice. This quick and non-verbal method of assessing vision provides a potentially cost-effective vision assessment strategy that addresses an important population health issue.

Retinal degenerative disorders are inherited diseases that affect tens of thousands of Canadians. The effects are devastating; severe vision loss or complete blindness occurs early in life, resulting in the loss of livelihood, mobility, and independence. There is no cure, and present treatments focus on easing the symptoms of blindness instead of preventing vision loss in the first place.

My research is focused on the prevention of vision loss by understanding how specialized structures in the light-sensing cells in the eye, called photoreceptor outer segments (OS), are made, and how defects in OS assembly result in photoreceptor death and blindness. Using genetically-modified frogs, I have replicated human disease caused by mutations in two genes, prominin-1 (prom1) and photoreceptor cadherin (prCAD). I have determined that these genes are necessary for OS organization, and am now working towards identifying their specific functions.

Identifying the roles of prom1 and prCAD will benefit scientists and patients.  It will further our understanding of how OS are built, a topic of great interest to visual scientists, and aid in the identification of novel therapies for some of the most common human retinal degenerative disorders.