Dr. Akira Shiraishi
CAAIF Research Fellowship in Type 2 Inflammation
supported by Sanofi Genzyme Canada
Dr. Partho Adhikary
Th2 inflammation-on-a-chip: Developing an ex vivo drug discovery platform for atopic diseases.
Atopic diseases are common allergic diseases such as eczema, asthma or hay fever. Skin and lung cells produce a factor, thymic stromal lymphopoietin (TSLP), which is known to be a main driver of such atopic diseases as it activates immune cells that further trigger inflammation. Hence, inhibiting this factor holds a great potential to treat atopic diseases. Currently, mostly large molecules, such as antibodies against TSLP are being developed, which however must be administered by injection and cannot be applied locally, for example as a cream. Drugs which can be applied locally offer several advantages such as less side effects, being more effective, and higher acceptance rates among patients. Hence, we are currently developing effective so called ‘small molecule TSLP blockers’ with the goal to be able to apply them locally onto the skin without needing any needles or injections. We already have identified a few very promising candidates, yet there is no model available to test its safety and efficacy. Hence, we will develop a ’human-on-a-chip’ setup which will allow us to test the promising compounds in complex and novel human-based setting without any animal models.
CAAIF Research Fellowship in Type 2 Inflammation supported by Sanofi Genzyme Canada
Dr. Nermin Diab
Point of care solutions to delayed Type 2-mediated drug
Chronic cough affects approximately 10% of the general population and is one of the commonest reasons for referral to secondary care. Unfortunately, there are no licensed treatments for this debilitating condition, which affects the social, physical and psychological well-being of patients. Asthma and Non-asthmatic Eosinophilic Bronchitis (NAEB) are known causes of chronic cough. An important feature of both these conditions is the presence of an inflammatory cell called the eosinophil which is found in the airways. The most common treatment for this is high doses of inhaled steroids, but when the cough becomes unbearable, repeated courses of oral steroids are administered. However, many patients have persistent cough despite this treatment and can develop significant steroid related side effects. Developing treatment for this condition is thus a major unmet clinical need.
Cough is a defensive reflex which is triggered by activation of nerves which are found in the airway lining. Recent evidence suggests there is a significant increase in eosinophils in the airways which sensitizes these nerves. This makes the nerves more easily activated leading to more coughing. If these eosinophils could be depleted and prevented to enter the airways then we predict that the nerves will be less sensitive and coughing will be reduced.
Mepolizumab is an injection medication, which blocks a key chemical that prevents the maturation and activation of eosinophils. It is a licensed medication which is currently used in patients with severe asthma to prevent severe asthma attacks. However, there has been no evidence to show whether this medication would improve coughing. The aim of this research project is to investigate whether mepolizumab reduces objective cough frequency in patients with eosinophilic airway diseases. The results of this study would result in a paradigm shift in the management of this challenging condition and provide patients hope of an improved quality of life.
CAAIF-Asthma Canada Graduate Student
Investigating the Effects of Rostral Fluid Shift and Obstructive Sleep Apnea on Airway Narrowing in Asthma
Asthma and obstructive sleep apnea (OSA) are very common breathing disorders that cause disability and poor quality of life. Asthma and OSA often co-exist but it remains unclear why. Our research group has established that fluid moving from the legs to the upper body during sleep contributes to cause and severity of OSA. My previous daytime study demonstrated that mimicking OSA draws fluid into the chest and increases small airway narrowing, providing strong evidence that fluid movement into the chest could link OSA and asthma. Therefore, I propose to investigate, first, the possibility that patients with both asthma and OSA may have more fluid moving into the chest and greater small airway narrowing overnight than patients with only asthma; and second, that treating OSA in asthmatics will prevent both overnight fluid moving into the chest and increase small airway narrowing. The outcome of my research could lead to a novel approach to diagnosis and treatment of co-existing OSA for some patients with asthma, especially those with poor asthma control in whom treating OSA might improve asthma control. Should my hypotheses prove correct, clinical trials could be designed to determine whether treatment of co-existing OSA in asthmatics can improve asthma outcomes.
CAAIF-Asthma Canada Graduate Student
Investigating epigenetic changes associated with prenatal air pollution exposure in the CANDLE study.
Prenatal air pollution exposure is associated with an increased risk of childhood asthma. While the mechanisms underlying this association remain unclear, researchers believe that environmental exposures become biologically embedded in epigenetic patterns, specifically DNA methylation (DNAm), during critical developmental periods. These altered patterns are thought to “reprogram” cell function, and ultimately influence health outcome. This research project will identify DNAm patterns associated with prenatal air pollution exposure at birth, and examine how altered epigenetic patterns evolve through childhood. All identified DNAm changes will be correlated with childhood asthma. However, we are most interested in the association between persistent DNAms changes and asthma, and persistent changes are more likely to influence health outcome than transient alterations. This analysis will provide insight into molecular pathways that are altered by prenatal air pollution exposure and contribute to asthma. Additionally, as we believe air pollution-induced DNAm changes arise from oxidative stress, this research will investigate if maternal diets higher in antioxidants (like vitamin C) can mitigate the effect of air pollution on child DNAm patterns. Together, this research will help clarify how prenatal air pollution exposure predisposes children to asthma, and begin identifying preventative measures.
CAAIF-Asthma Canada Graduate Student
Dr. Andrew Kouri
Exploring the influence and perspectives of older adults in the development and testing of mobile health interventions in airways disease
Mobile health (mHealth) technology using smartphones and tablets is increasingly being incorporated into the care of asthma, one of the most common chronic respiratory diseases in Canada. mHealth can facilitate asthma self-monitoring and self-management, which are essential to effective asthma care.
Given that the prevalence of asthma is growing in older populations in Canada as the population ages overall, and that older patients with asthma are disproportionally negatively affected by asthma compared to younger patients, older adults with asthma may significantly benefit from the promises of mHealth technology.
However, little is currently known about the effectiveness and acceptance of mHealth tools in older adults with asthma, and studies in other conditions like diabetes suggests that there may be important barriers that need to be overcome before mHealth tools can help older populations. My PhD thesis projects seek to determine if and how mHealth tools are currently being developed with older patients in mind, and to achieve a better understanding of the needs and perspectives of older adults with asthma in their use of mHealth technology. This understanding may hopefully be used to design and implement more effective mHealth solutions for older adults with asthma.
CAAIF Top 10 Challenge Food Allergy Research Grant
Dr. Jennifer Protudjer
NOURISH: patieNt-Oriented research to Understand and addRess Inequities of food accesS and insecurity amongst Households managing food allergy
Over 3 million Canadians live with food allergy. These people must avoid the food to which they are allergic in order to prevent a potentially fatal allergic reaction. Avoidance comes at a cost, both in terms of psychosocial health, and financial costs. Before the pandemic, households managing a food allergy spent, on average, $2500 more per year on food, than households without food allergy. Preliminary data from our group suggest that these excess costs are even higher during the pandemic. At the same time, food prices have increased by almost 10% and unemployment has doubled. It is not surprising, then, that households managing food allergy report the buying foods with a “may contain” label because of a lower price point than allergy-friendly foods, and that nearly one in five households with food allergy also report food insecurity. In the proposed project, we seek to further understand and address the inequities of food access and insecurity among families with a child, with a food allergy.
CAAIF Research Fellowship in Immunology Supported by Takeda Canada
Dr. Daniela Stanga
A Prime Editing-Based System for Modeling Primary Immune Disorders
Diagnosis of inborn error of immunity (IEI) has recently seen a sharp increase, primarily due to the proliferation of genomic methods that clinicians now use to investigate their patients' genetics. The identification of an IEI as a cause of allergy, autoimmune disorder, or susceptibility to infection has a profound impact in determining the best treatment option. However, many variants identified by current genomic technology cannot be definitively linked to the pathology presented by the patient. Variants of unknown significance (VUS), thus, present a considerable challenge to making the correct diagnosis and providing effective therapy. Hence, we are currently developing a cellular model with the ability to test any genetic variant for its ability to result in an IEI using prime editing, a method to introduce small insertions, deletions, and base-swaps in DNA that has been derived from CRISPR-Cas9 systems. Using this model, we will investigate the molecular basis of the immune dysfunction associated with the mutations in RIPK1, a master regulator of cell death, and inflammation which dysfunction can provoke degenerative and inflammatory disorders.
By using prime editing to quickly re-create any given variant in a standard human cell line, validate the edit and experimentally determine the immunocompetence of the edited cells, this project will lay the groundwork for personalized medicine by providing a method that can rapidly investigate any variant identified.
CAAIF-Miravo Healthcare Research Grant in Allergic Rhinitis or Urticaria
Dr. Anne Ellis
Allergic Rhinitis Microbiome Study (ARMS): Investigating the nasal microbiome of allergic rhinitis using nasal allergen challenge
Allergic rhinitis(AR) is a disease that affects 25% of Canadians. AR is caused by an allergic reaction to airborne allergens that trigger symptoms like those seen with the common cold. Although some studies have suggested a link between allergies and the microbiome, the combined genetic material of microorganisms in an environment, there is currently little understanding of how microbiome changes can lead to disease in the nose. We have demonstrated that we can induce AR using a controlled nasal allergen challenge(NAC) model and developed methods to sample the local microbiome concurrently. This project proposes to use these tools to determine precisely how changes in the nasal microbiota affect AR via the collection of clinical and biological outcomes. Recent studies have shown that immunoglobulin(Ig)-E levels, a mediator of AR, are associated with specific microbiomes. Therefore, the total IgE levels will also be measured in this study.
Despite the therapeutics available for AR, rates of treatment dissatisfaction are high(~60%). This poor rating may because available therapies primarily treat AR symptoms and not the underlying factors driving disease progression. Our research will help clarify the role of the microbiome in AR and facilitate the development of novel treatments for this increasingly common disease.
CAAIF-AVIR Pharma Research Grant in Eosinophilic Esophagitis
Dr. Stephanie Erdle
Using the OX40 assay to identify new onset or worsening eosinophilic esophagitis (EoE) in children undergoing food allergy immunotherapy (FAIT)
Eosinophilic esophagitis (EoE) is an increasingly common childhood disease caused by delayed-type allergies to specific foods. Food allergy immunotherapy (FAIT) is a new treatment for patients with immediate-type food allergy. One of the potential risks of FAIT is the development of EoE. The only accurate test available to diagnose and monitor EoE is endoscopy with biopsy, which carries significant procedures risks and requires a general anesthetic and access to a tertiary care centre. Our goal is to develop a simple blood test to identify immune responses to specific foods to monitor for the development or worsening of EoE in children undergoing FAIT. This has the potential to save children multiple general anesthetics and operating room procedures. In addition, this will improve access to the diagnosis and monitoring of EoE for children living in remote and rural regions.
CAAIF-Immunodeficiency Canada Research Fellow/Early Investigator Award in Immunodeficiency
Dr. Akira Shiraishi
Novel genetic aberrations underlying inborn errors in immunity: A study of SLC19A1 and RASAL3 genes
The immune system plays a critical role in protecting the body from microbial infections. This complex and highly regulated system consists of multiple specialized cells and molecules that act together in harmony. Importantly, defects in genes involved in any part of the immune system can lead to immunodeficiency. This presents clinically as increased susceptibility to infections, autoimmunity and predisposition to cancer. Inherited immunodeficiency affects 1-2% of the population and may present at any age, starting from infancy. Importantly, between 35-40% of cases result from currently unknown genetic mutations, and the reasons for disease remain unclear in many others. Thus, treatment options remain significantly suboptimal.
Using next generation sequencing techniques, we recently identified two potential disease-causing genetic mutations leading to novel immunodeficiency. I propose to investigate the impact of these aberrations on the immune system. This will help to improve our understanding of how the gene functions in health and disease, and perhaps expand the available treatment options for patients to improve quality of life.