Allergic diseases are reaching epidemic proportions, now affecting 1 in 3 Canadians. Allergies are inappropriately high immune responses against innocuous allergens. Understanding why the immune system reacts in this way is crucial to identify new drug targets.
Proteases are enzymes that cut other proteins from allergenic sources, for example dust mites and mould. Proteases are potent triggers of allergic responses. However, an understanding of the proteins they cut and how they fit into the global picture of allergic responses is lacking.
Dr. Machado Hernandez’s research will work to identify the key proteins involved in allergic responses triggered by proteases, or cut by proteases, using an innovative and highly advanced technique known as “degradomics”—a method of uniquely identifying the cut ends of proteins by purifying them from the rest of the protein. As cuts are formed only during active disease, these segments are highly valuable as disease markers to develop new clinical tests and identify new drug targets.
The roles of these proteins and their cut products will be deciphered by biochemical and immunological studies to reveal the damaged proteins and proteases that can be targeted with new drugs to improve health outcomes and ensure sustainable health care costs.
Oxidative stress (OS) describes the occurrence of reactive oxygen species (ROS), chemicals that cannot be balanced by the body’s antioxidant defenses. OS can occur in every cell of the body and is linked to an increasing number of diseases.
Recently, several reports indicated the influence of OS on transient receptor potential (TRP) channels that are expressed in various cell types and involved in a broad array of functions. More recently, it was discovered that redox reagents can modulate the activity of TRPM3, a nociceptor channel, involved in the detection of pain and heat. TRPM3 is highly expressed in the brain, but no functional role has been established for TRPM3 in this area so far. However, the brain possesses a high oxygen content and diseases like epilepsy have been linked to the occurrence of OS.
Dr. Held’s research will investigate the role of TRPM3 in the brain and in brain-related diseases that induce oxidative stress. The outcome of this project will improve our understanding of TRPM3 function and its role in cell stress-inducing pathological conditions, which could help to develop new treatment options.
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
Despite major advances in our understanding of the mechanisms behind the body’s immune response against cancer, several obstacles limit the success of immunotherapy as a cancer treatment. In particular, the physical exclusion of immune cells from tumour beds is associated with poor prognosis and a limited response to immunotherapy.
Dr. Rodriguez’s research will address this issue by investigating the mechanisms underlying the exclusion of immune cells in ovarian cancer. The results will lead to more effective treatments to help the immune system eradicate ovarian and related cancers. The findings of this research will lead directly into first-in-human clinical trials for patients with ovarian cancer and related malignancies.
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.
Lung cancer is the leading cause of cancer-related death in Canada. A major reason for the poor prognosis is the lack of effective drugs for treating advanced tumours.
New understanding of the mutations driving lung cancer has led to the development of targeted therapies that selectively inhibit mutated genes, leading to rapid cancer regression in specific subsets of patients. However, while these therapies improve patient survival and quality of life, they are not curative as all patients develop drug resistance.
While some causes behind this resistance have been defined, others remain elusive, and are becoming more prominent with newer generations of drugs. A major example is tumours changing how they look—shifting from one type of lung cancer to another—but what causes this is still not clear.
Dr. Inoue’s research will test whether treatment with targeted therapies creates the environment that allows tumours to “change their skin” and continue to grow in the presence of drugs. The goal is to determine the genes involved in this shift and prove they are responsible for drug resistance. This will lead to new therapeutic strategies that will provide longer-term survival benefits for lung cancer patients.
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.
Lymphoma is a cancer of the lymphatic system where tumours develop from abnormal growths of white blood cells. Non-Hodgkin Lymphomas (NHL) are the fifth most common cancers diagnosed in Canada. Of those, diffuse large B-cell lymphoma (DLBCL) is the most common.
Numerous studies have furthered understanding of the internal chemical mechanisms of communication (signaling pathway) altered in malignant cells. However, the tumour is not only composed of cancer cells; the cancer cells are surrounded by a multitude of other cells and molecules (also known as the tumour microenvironment) that contribute to the development of the tumour. Although some improvement has been made in the treatment of lymphoma, current standard therapies still fail to cure a significant proportion of patients for which novel therapeutic agents have to be developed. More investigations are needed to discover new therapeutic targets that will lead to the development of more effective drugs to improve patient outcomes.
Dr. Viganò aims to fill these knowledge gaps in DLBCL development and treatment. In particular, her research will explore the influence of mutations in the Janus kinase-signal transducer and activation of transcription (JAK-STAT) signaling pathway on the tumour microenvironment. She will also investigate new biological targets to inform the development of novel therapies.
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.
