The discovery of antibiotics was one of the greatest advances in modern medicine, enabling control of infections. However, bacteria can develop antibiotic resistance over time, and become less sensitive to antibiotics. Without effective treatments, infections by these organisms can lead to prolonged illness, and routine surgeries can become life threatening. The lack of new antibiotics to combat the rapidly growing number of multi-drug resistant (MDR) organisms has become one of the most serious global health concerns. There is an urgent need to develop new therapeutic strategies against MDR organisms.
Dr. Choi’s research will investigate the potential use of a group of natural molecules known as host defence peptides as an alternative therapy to treat chronic infection caused by MDR organisms. The advantage of these peptides is that they do not directly target microorganisms; instead, these molecules promote the body’s immune system to fight against infections. This unique ability prevents microorganisms from developing resistance towards the peptides.
Results from this research will be an exciting example of alternative therapy to treat antibiotic resistant infections.
End of Award Update: October 2022
Most exciting outputs
One of the most exciting outcomes is to have the opportunity to present my results at an international conference—the Gordon Research Conference—and establish networks with scientists across the world.
Impacts so far
The Michael Smith Health Research BC/ Lotte & John Hecht Memorial Foundation Research Trainee award allowed me to focus on my project to develop alternative therapeutic strategies against multi-drug resistant organisms, especially during the COVID pandemic.
Potential future influence
The award gave me opportunities to attend various conferences where I presented my work, met with researchers whom I can learn from to advance my knowledge and skills, and built supporting networks, all of which are invaluable for my career goal as a researcher.
Next steps
We are in the process of writing a manuscript on utilizing lung organoid model for screening antimicrobial and immunomodulatory therapies against Pseudomonas aeruginosa infection.
Useful links
There are 62,000 strokes in Canada each year–one every nine minutes–and 405,000 Canadians are living with the effects of stroke. Stroke rehabilitation is a large field with a need for further research and treatment development.
Dr. Balbi will investigate brain stimulation and movement-based stroke rehabilitation by studying brain activity and forelimb movement in mice stroke models.
The aim is that this research will yield optimal parameters and inform treatment in humans with regards to intensity and frequency of rehabilitation, specific passive movements and brain stimulation, and ultimately will allow human-translatable stroke treatments to be piloted in a larger sample.
The frontal cortex (FC) of the brain plays a critical role in higher cognitive functions including attention, working memory, and planning future goal-directed actions. Cognitive deficits arising from deceased neural activity within the FC (hypofrontality) are features of many forms of mental illness, including schizophrenia, attention-deficit hyperactivity disorder, dementia and addiction. Neurochemical, physiological and pharmacological research implicates reductions in the function of key neurotransmitter systems: catecholamines, glutamate and GABA.
Dr. Axierio-Cilies and team have developed a novel compound that alters key subtypes of glutamate receptors. Using optogenetic (light) stimulation of dopaminergic and glutamatergic pathways, this research will assess the usefulness of this novel compound for the treatment of clinical conditions that are attributed to a reduction of neurotransmitter function within the FC as part of a multifaceted drug development program.
Antibiotics are arguably the most important and successful medicines. However, the frequent growth of bacteria as biofilms, bacterial communities that grow on surfaces in a protective matrix, is of great concern. Biofilms account for two thirds of all clinical infections and are especially difficult to treat with conventional antibiotics. They are a serious problem in trauma patients with major injuries, as well as individuals with implanted medical devices.
The Hancock lab has developed novel synthetic peptides that have demonstrated a superior ability to combat bacterial biofilms. These agents work against pre-formed biofilms, show synergy with antibiotics, neutralize the universal stress response in bacteria, and work against high-density bacterial abscesses in animal models. These small peptides are promising biofilm-specific agents.
Dr. Pletzer’s research will study the mechanisms of these peptides and how they interact with and aid antibiotics as this novel treatment moves towards clinical development.
In order for skeletal muscle to contract, signals alert the muscle cells to release calcium from their internal stores. The skeletal muscle ryanodine receptor (RyR1) acts as the essential gatekeeper for these calcium pools. A single mutation within a person’s RyR1 can result in an unpredictable and life-threatening complication called malignant hyperthermia (MH).
MH is a disease that causes uncontrolled muscle contraction and an extreme increase in body temperature when exposed to general anesthetics. While our understanding of RyR1 is improving, there is still much to learn about the relationship between the protein’s structure and how small molecules like anesthetics alter the channel’s activity.
Dr. Woll’s research will look to identify the binding sites for anesthetics within normal and MH mutant RyR1 in order to determine and compare the interactions and their consequences. To accomplish this, she will employ photoactive analogs of the anesthetics to identify binding sites within both RyR1s and determine the impact of binding on the ion channel’s conformation using cryo-electron microscopy.
Ultimately, this research will provide a strategy for the advancement of scientific methods, further define the transitions that occur within RyR1, and determine how anesthetics impact the channel’s function.
Dr. James Johnson is one of five BC researchers leading teams supported through the British Columbia Alzheimer’s Research Award. Established in 2013 by the Michael Smith Foundation for Health Research (MSFHR), Genome British Columbia (Genome BC), The Pacific Alzheimer Research Foundation (PARF) and Brain Canada, the goal of the $7.5 million fund is to discover the causes of and seek innovative treatments for Alzheimer’s disease and related dementias.
Alzheimer’s disease (AD) – the most common form of dementia – is a fatal, progressive and degenerative disease that destroys brain cells, causing thinking ability and memory to deteriorate.
One percent of AD is the early-onset type that runs in families. While extensive studies of these forms of the disease have revealed the genes that cause them, the most common, late-onset forms of AD are understudied and poorly understood at the level required for therapeutic intervention.
Studies have shown links between Alzheimer’s disease and obesity, altered fat metabolism, insulin and diabetes, with diabetes increasing the risk of suffering from AD by 30-65 percent. Scientists have also found the brain produces a small amount of insulin with reduced levels in the brains of AD sufferers. While the function of brain insulin is a mystery, evidence suggests reduced brain insulin could play a role in Alzheimer’s disease.
Dr. James Johnson, a professor in the Departments of Cellular and Physiological Sciences and Surgery at the University of British Columbia (UBC), further found in preliminary studies that high-fat diets reduced brain insulin production. The goal of Johnson’s continuing research is to answer the key question: is the loss of brain insulin alone enough to cause cognitive impairment? Johnson will test the hypothesis that brain-produced insulin is a critical factor for the survival and function of brain cells in the context of both a genetic change that increases Alzheimer’s risk and a diet that increases Alzheimer’s risk. Using mice models lacking brain insulin, Johnson’s team will assess their ability to learn and study how their brains are reprogrammed. Insulin will be correlated with Alzheimer’s-like changes in human brains.
Information on the role and mechanisms of brain insulin through Johnson’s pioneering research has the potential to advance understanding of AD and contribute to an eventual cure. Identifying the link between diet, insulin and Alzheimer’s disease could also enable earlier diagnosis and inform strategies for Alzheimer’s prevention. Furthermore, the findings may shed light on much-needed new drug targets for Alzheimer’s disease or possibly re-purposing existing diabetes drugs.
Dr. Christian Naus is one of five BC researchers leading teams supported through the British Columbia Alzheimer’s Research Award. Established in 2013 by the Michael Smith Foundation for Health Research (MSFHR), Genome British Columbia (Genome BC), The Pacific Alzheimer Research Foundation (PARF) and Brain Canada, the goal of the $7.5 million fund is to discover the causes of and seek innovative treatments for Alzheimer’s disease and related dementias.
Alzheimer’s disease (AD) is the most common form of dementia, accounting for almost two thirds of total cases. There are currently no successful treatments, making the discovery of effective therapeutic interventions critical.
The brain contains billions of neurons (nerve cells), and substantially more non-neuronal cells called glia. Astrocytes, the most abundant type of glial cells, closely interact with neurons to control the transmission of electrical impulses within the brain. The major disease hallmark of AD is cognitive decline linked to neuronal wasting, impairment and finally, death.
Dr. Christian Naus, a professor in the Department of Cellular and Physiological Sciences at the University of British Columbia (UBC) and Canada Research Chair in Gap Junctions and Neurological Disease, studies the molecular and cellular mechanisms by which astrocytes lose their ability to support neurons that are vulnerable to destruction in Alzheimer’s disease, with the aim to identify new drugs to aid in treatment.
Naus’ team examines a unique set of cellular channels in astrocytes and neurons formed by special proteins, called connexins and pannexins. These channels help control the environment in which the cells of the brain must function by allowing a variety of small molecules to pass freely from one cell to another, and allowing them to coordinate cellular responses to various signals. However, when these channels stop working properly, they can become damaging to the environment thus compromising the normal functions of neurons. Naus’ research explores the role of these channels in neurons and astrocytes in order to identify how to manipulate these channels to provide protection for neurons in cases of disease, such as AD.
The outcome of these studies will contribute to the potential identification and development of new drugs that will not only target neurons, but also enhance the ability of astrocytes to protect neurons that are vulnerable to cell death in AD.
Positron emission tomography (PET) imaging provides the most accurate and sensitive detection of cancer in patients. Yet PET is challenged by cumbersome methods that impede the clinical production of PET imaging agents and diminish their distribution and use. A critical unmet need for PET imaging is access to user-friendly methods to simplify and speed up time-sensitive radiosynthesis to deliver imaging agents to clinics.
Dr. Perrin and team have invented a chemical tag that lets chemists turn any molecule into a PET imaging agent. Now, Dr. Perrin will deploy this method to develop commercial products for imaging prostate cancer, which affects 23% of Canadian men and demands the use of PET imaging for early detection.
These tags create novel prostate cancer-specific probes which allow tumours to be labeled in record time and in a user-friendly manner for clinical radiosynthesis, and provide superior pre-clinical mouse images. These must be tested and evaluated before progressing to human trials and clinical production.
This innovation could allow prostate cancer to be detected earlier and better, increasing cure rates and the long-term survival rates of this deadly and common disease.
Chronic rhinosinusitis (CRS) is an inflammation of the nasal sinuses, and is one of the most common medical complaints in North America, affecting up to 16% of the population. It leads to around 24 million physician visits per year, with an aggregated cost of more than $6 billion. Although the pathophysiology behind CRS isn’t fully understood, it appears to be largely triggered by bacterial biofilm infections. The microbes associated with these biofilms are diverse, and treatment options (including antibiotics) are limited and often fail to cure the disease.
Dr. Hancock will develop a novel topical intranasal treatment for CRS, based on anti-biofilm peptides. These peptides have already been shown to kill multiple species of bacteria in biofilms, especially the most resistant pathogens. Dr. Hancock has screened a library of peptides for their efficacy against multiple bacterial species, including several significant CRS pathogens.
Dr. Hancock will select a lead and backup anti-biofilm peptide with the most efficacy against sinusitis bacteria in their biofilm state, minimal toxicity when provided topically, and with optimal anti-inflammatory properties both in vitro and in animal models.
This research could directly lead to a new therapy for CRS, which would trigger immediate clinical and commercial development. Dr. Hancock has brought on partners for the first two years—Dr. Armin Javer of the St. Paul’s Sinus Clinic, and the Centre for Drug Research and Development, and has already identified a prospective development partner, Victoria-based company ABT Innovations Inc.
Metastasis, which is the spread of cancer cells from a primary tumor to other areas in the body, remains the main cause of cancer related death. Awareness of the clinical importance of metastasis and our basic scientific understanding of the metastatic process has improved substantially over the past few decades. However, many aspects of metastasis are still not well defined and our ability to identify patients at high risk for cancer spread is limited. In addition, cancer treatments are not metastatic-specific, so despite aggressive treatments many patients still progress to a metastatic disease state. Dr. Williams' research aims to address these issues by identifying aggressive disease early and uncovering key regulators of metastasis for inhibitor development.
Cancer cells are constantly shedding small fragments, which can be readily detected in the blood. This project will develop a test that analyzes these fragments, identifying cancer patients and determining the aggressive nature of their disease. It also aims to uncover how cancer cells move and grow within the body by forming tiny 'feet-like' structures called invadopodia. Understanding their role in cancer progression will shed light on how cancer cells move and grow within the body, validating them as targets for metastatic inhibitor development. Overall, this research program will make powerful strides towards ending metastasis, the most significant cause of cancer mortality.
