Asthma is the most common chronic disease in childhood and continues to increase through adulthood. When a patient has asthma, airways in the lungs become swollen and tight causing symptoms such as shortness of breath, wheezing, chest tightness, and cough. Current therapies for asthma relieve symptoms but do not restore airways back to normal function or cure the disease.
Asthma is influenced by many different genetic and environmental factors, so despite having many drugs available and more in development it is extremely difficult to match patients to the right treatment. To better match patients to the right therapies we need to understand the process by which allergies lead to asthma.
This project aims to find new ways to predict the response of asthmatic patients to existing and new drugs by better understanding how allergies cause asthma symptoms. We will look at several molecules in the blood known to be important in asthma, and measure them in airway tissues and cells obtained from asthmatic and non-asthmatic patients. This will give us a much better picture of what these important molecules are doing directly at the source of the allergic inflammation.
Health information technology (HIT) safety is an important issue internationally. Clinician organizations (e.g. American Medical Association, Institute of Medicine) and health informatics organizations (e.g. Digital Health Canada) have made statements about HIT safety concerns and their implications.
This research will encompass several interconnected studies to develop a comprehensive strategy to improve HIT safety in Canada and internationally, to be conducted in a series of phases.
- Phase 1 of the research will involve a systematic review of HIT safety issues and approaches to improving the safety of HIT as well as its safe use.
- In Phase 2, national incident reporting on HIT safety will be studied and analyzed from three countries (Canada, Finland and the United States).
- Phase 3 will involve clinical simulations to understand how technology-induced errors arise and to identify best practices that could be used to improve and educate health professionals on HIT safety.
Bladder cancer is the fifth most common cancer, yet it remains understudied and we are only now making strides in understanding it’s molecular make-up. Recently we and others have discovered that loss of the cell surface receptor Notch-1 drives growth of some bladder cancers, while increased Notch-2 activity drives growth of other bladder cancers. Here we aim to determine how Notch-1 and Notch-2 can lead to such differing effects on cancer growth even though they share many features. From this we aim to design a new drug to inhibit Notch-2.
We will:
- Create a mouse model that over-expresses Notch-2 in the bladder. We expect this will cause bladder tumours to form.
- Use advanced techniques to study the differences between Notch-1 and Notch- 2 signaling that make them have such different effects. We will especially investigate how each Notch protein controls the reading of genes in the cell nucleus.
- Develop a new a new drug to inhibit Notch-2 using computer-aided drug design.
End of Award Update – April 2024
Results
We have identified a candidate Notch-2 inhibitor that requires further testing in pre-clinical models before potential testing in patients with bladder cancer.
Impacts
Our work has explained an important pathway that drives growth and progression of bladder cancer in some patients.
Potential Influence
This new inhibitor could represent a novel way to treat bladder cancer.
Next Steps
We will publish the results on Notch when completed.
Primary immunodeficiencies (PIDs) are a group of conditions in which part of the immune system is either missing or does not function normally. Those affected by PIDs may suffer from recurrent infections, autoimmune disease (where the immune system attacks the body's own tissues), and certain cancers. These conditions are not rare; affecting 1:2,000 to 1:10,000 people, with nearly half of cases diagnosed in adulthood. Too often, adults with PIDs undergo a painful journey that spans decades in search of a diagnosis. Without knowing the cause of their immune deficiency, adults with PIDs may not receive life-changing treatment.
Our research program will address these challenges using precision medicine: an exciting way of identifying the cause of the disease and finding treatments that specifically target the underlying problem. We will perform next generation sequencing, a method to quickly read genetic material, on adults with PIDs where the underlying cause is undiagnosed. If a new change in a gene (mutation) is identified, we will perform specialized experiments to prove that the mutation is indeed responsible for the patient's symptoms. We will then look for targeted treatments to address the specific cause of that patient's illness.
By harnessing the power of personalized genetics and precision medicine, our goal is to improve outcomes for adults suffering from PIDs.
Empty Nose Syndrome (ENS) is thought to be an unusual outcome of sinus surgery due to excessive loss of nasal tissues, particularly from a pair of structures called the inferior turbinates. Turbinates usually function to warm and humidify air flowing into the nose. Patients with ENS often have severe nasal symptoms and develop very poor quality of life as well as mental health problems. As a result of these mixed symptoms, ENS patients are often misdiagnosed, mismanaged, and left to their own devices.
Our research has shown that ENS patients can be identified based on specific clinical symptoms and imaging of the sinuses. We have also found that by rebuilding structures within the nasal cavity known as inferior turbinate augmentation (ITA) we can greatly improve nasal function. However, little is known about the specific changes in nasal function with ENS, how mental health problems develop, or how to best treat these patients.
Our objectives are three-fold: 1) to measure the patterns of nasal airflow and sense of smell present in ENS patients by using computer analysis and smell testing; 2) to understand how ITA might improve function in ENS patients by measuring nasal airflow and sense of smell before and after surgery; and 3) to study the impact of ENS on mental health using depression and anxiety survey scores, and then measure the change in these scores after ITA to study the relationship between the nasal and mental health problems in ENS. By studying the relationship between nasal and psychiatric symptoms in ENS we will both improve our understanding of how this syndrome develops and improve our understanding of how surgical interventions might help mend these symptoms.
Patients with human immunodeficiency virus (HIV) are now living to older ages thanks to effective anti-HIV medicines. Despite these gains, many of them suffer from chronic lung disease that greatly impacts their ability to carry out their daily activities and impairs their quality of life. The type of lung disease they face is similar to what longtime smokers develop, a progressive narrowing of the airways and destruction of the lung. However, in HIV, the process appears to be accelerated and more severe. It’s not unusual, for instance, to see patients in their 30s and 40s develop this lung disease (which is approximately 30-40 years earlier than expected). Also, it’s not unusual for HIV patients who have never smoked before to develop this kind of disease. Unfortunately, the traditional medications we use to treat lung disease often interact with anti-HIV medicines, causing severe side effects. Management of breathing symptoms in HIV patients is therefore difficult and it is imperative that we find better agents to combat lung disease in this population. Only by understanding what causes and drives this lung injury process can this goal be achieved, though.
Multiple studies have now shown that smoking alone cannot explain the lung disease phenomenon in HIV. I believe that HIV injures the lung in a two phase process. First, the virus directly breaks down the protective layer of the airway known as the epithelium. Second, over time, as patients develop repeated lung infections due to their weakened immune systems, the bacterial community of the lung or microbiome shifts. I believe that this community disruption results in molecular changes that age the lung faster. My approach is to perform an in-depth investigation into the epithelium of the airway using two innovative methods. To explore the injury that HIV inflicts on the airway, I have created a novel model of the HIV airway using HIV-infected cells co-cultured on a cell culture model of the airway epithelium. We will use this model to see how HIV-infected cells break down the protective barrier of the lung. To explore the shifts in the microbiome, I have collected airway cells from HIV-infected and uninfected patients to not just describe what bacteria exist in the airway but also to determine what effect the community differences between the two groups have on the function of genes in the cells. We will measure how ‘old’ these cells are and compare these findings to uninfected patients.
End of Award Update: December 2022
Most exciting outputs
The work of my laboratory was the first to detect accelerated epigenetic aging and methylation disruptions in the HIV airway epithelium, work that has now been published in the American Journal of Respiratory and Critical Care Medicine, and eBioMedicine.
Impacts so far
These insights into accelerated aging in the HIV airway epithelium provide clues into why people living with HIV may be prone to developing chronic lung diseases such as Chronic Obstructive Pulmonary Disease or COPD.
Potential future influence
Our work highlights the importance of accelerated aging in HIV, even in patients with well controlled infection. Reversing these aging mechanisms may be critical in the prevention or attenuation of airflow obstruction in this population.
Next steps
We are continuing to explore mechanisms of early aging in the HIV airway using novel technologies such as magnetic resonance imaging, optical coherence tomography, and single cell sequencing.
Useful links
Radiotherapy (RT) is a common and cost effective treatment for patients with painful bone metastases (BoM). Complex and lengthy RT courses are increasingly used for BoM, despite substantial evidence and Choosing Wisely Canada guidelines recommending the use of single fraction RT (SFRT) over lengthy courses. Reluctance to adopt SFRT is based on lack of evidence of its effectiveness in patients ineligible for trials, such as those with poor performance status and BoM complicated by fracture or neurological compromise. Unfortunately, guidelines recommending SFRT use in Ontario did not lead to a durable change in practice. Therefore, evidence of SFRT’s effectiveness in a broad population is necessary, including patients ineligible for trials. Comparison of SFRT to lengthier and complex techniques, such as intensity modulated RT (IMRT) and Stereotactic Ablative Body RT (SABR), will build a population-level evidence base to support increased prescription of SFRT in BC and across Canada.
My research team has demonstrated it is feasible to collect and use Patient Reported Outcomes (PRO) on a population scale in BC. We used these PRO to demonstrate that pain improvement is similar between SFRT and weeklong RT courses, the results of which have led to increased prescription of SFRT across all six BC cancer centres. This gained international attention and the Canadian Partnership for Quality Radiotherapy (CPQR) has since invited me to lead PRO collection across the Canadian RT community. Under the current proposal, we will apply a similar integrated knowledge translation (iKT) approach used in our BC-based research to demonstrate evidence for SFRT on a population-level.
Our primary KT goal is to use our research results to increase evidence-based prescription of SFRT. As we did in BC, we will integrate nursing, radiation therapy, and oncology into all stages of PRO collection and comparison between treatments, with subsequent educational outreach and centre-specific interactive small group discussions of research results. We will engage with various levels of health government, leverage our existing relationship with CPQR and the Canadian Partnership Against Cancer, and create an advisory committee of key stakeholders including policy makers, oncologists, and allied health professionals from each province. Impact evaluation of end-of-grant KT activities will focus on reach, collaboration, practice change indicators, and behaviour changes to increased use of SFRT.
Each year in Canada, road trauma causes over 2,000 deaths and 10,000 serious injuries. Disability after an injury is a major public health concern, but the long term health outcome after road trauma is poorly investigated and based mostly on older research that does not reflect modern vehicle safety features or modern medical treatment. In addition, there is almost no research that helps health care providers know which patients are most likely to have a bad outcome following a crash, making it difficult to provide them with the care they require. For policy makers, it is important to know the health care costs and lost productivity that results from road trauma, but this information has not been studied. My study will provide this missing information.
My team will interview patients who visit an emergency department after a traffic crash, including pedestrians, cyclists, and motorists. We will ask about their general health before the crash, the injuries they had from the crash, and other details of the crash. Repeat interviews at 2, 4, 6, and 12 months will ask about problems they had since the crash, including pain, ability to go about their usual activities, and return to work. We will also ask about the medical care they required after the crash.
This study will help doctors and nurses know how quickly people recover from their injuries after a crash and which patients are likely to have long term health problems. It will also describe the medical treatment that these patients require and how much work they miss. This information will give a better estimate of the true cost of road trauma, and may help policy makers decide how much funding to devote to crash prevention programs or to treatment programs for crash victims.
Atrial fibrillation (AF) is the most common heart rhythm disorder. With an aging population, the number of people with AF is expected to rise dramatically. People with AF are twice as likely to die, are five times more likely to have a stroke, can develop worsening heart muscle function, and have a lower quality of life. We have learned that a person's genetic makeup, or DNA, has a major impact on their risk of developing AF; but we have a limited understanding of why, or how to use this information to treat people in a safer and more effective way. People with AF first receive drugs to control their irregular heart rhythm. Even people who have procedures to treat AF are also prescribed drugs. This is particularly important in the group of patients who have persistent AF, who require electrical or chemical therapy to change their heart rhythm, as the success of surgical procedures in this population is well below 50%. Unfortunately our current drugs are generally ineffective, and can be unsafe, with little progress in drug development over the last two decades.
With these challenges in mind, the first goal of my research program is to identify and understand the genes that play a role in the development and progression of AF, and determine which are most common and most important in the Canadian population. To do this, I am gathering a biobank of AF patients and performing the largest scale detailed genetic testing in this population to date. I am also focused on understanding the effect that genes can have on the safety and efficacy of rhythm controlling drugs, and have already started a trial, funded by the Canadian Cardiovascular Society, that will link a person's genetic makeup to these important outcomes. I will then be able to take this large clinical and genetic data set to the laboratory where we have developed the unique ability to generate patient-specific stem cell disease models of AF. The ultimate goal of my research program is to directly tailor therapy for AF patients based on their genetic makeup, using information from clinical research and personalized disease modeling.
Pancreatic cancer kills almost 5,000 Canadians each year and if progress is not made to improve outcomes, the annual number of deaths will double by 2030. In 80% of patients, the cancer has spread at the time of diagnosis, and is not operable. Most of these patients die within one year due to the lack of effective therapies and the fact that clinicians have no clear guidance on which existing treatment option would work best for individual patients.
Precision medicine in cancer has gained a lot of attention in the last decade, as it may provide the best approach to treating tumours on an individual basis. Cancer treatment does not benefit from the one-size-fits-all approach because individual tumours, even if affecting the same organ, are biologically different, which can impact their response to treatment. Tumour subtyping, a method by which scientists identify the unique characteristics of individual tumours, is critical for precision medicine enabling personalized treatment based on the tumour's specific biological traits. Advances in the understanding of cancer subtypes have revolutionized treatment in multiple cancers, but we have yet to uncover pancreatic cancer subtypes that can help with treatment decisions.
Our goal is to define clinically meaningful pancreatic tumour subtypes, and study their impact on tumour aggressiveness and response to treatment. These findings will be rapidly translated to the clinic to have immediate impact on treatment selection for patients. We will perform detailed genetic and molecular analysis of patient tumour samples to investigate the distinct molecular characteristics. The patients will be enrolled in a clinical trial at the BC Cancer Agency and will be provided with detailed and cutting edge analyses of their tumours to help the clinical team guide further therapy decisions.
Currently, over 90% of diagnosed pancreatic cancer patients are not expected to survive five years. Our program has the potential to dramatically change the trajectory of pancreatic cancer and improve outcomes for thousands of Canadians diagnosed with the disease.
