Early Career Researcher Award in Asthma
Dr. Cristina Longo
Treating Asthma by Integrating Learning Algorithms with Omics
Research: Moving toward Automated High-Dimensional
Endotyping in Children (TAILOR-MADE)
Asthma is a common lung disease in children, which can cause severe breathing problems and affect their quality of life. When asthma symptoms happen, many kids will visit their doctor for a diagnosis and treatment. Doctors often treat asthma symptoms with medicines that you inhale. A major problem is that these medicines do not always work. This is because asthma has many different disease processes that need targeted treatments. Although we do not know much about these disease processes, we can understand more by collecting biological samples, like blood, breath, or saliva, and analyzing them with new technologies. These samples contain millions of signals or ‘biomarkers’ that can help us discover new disease processes for childhood asthma. However, this large amount of data makes it challenging to find which biomarker might be important. We now have advanced computer tools, like machine learning, that can help us address this ‘big data’ problem. My research program uses machine learning to discover important biomarkers and different disease processes in children with asthma symptoms that can help doctors predict their response to treatment. This will help doctors identify which children will benefit from treatment or develop new medicines for those that will not benefit.
This award was jointly funded by Asthma Canada, AstraZeneca Canada, the Canadian Allergy, Asthma and Immunology Foundation (CAAIF), the Canadian Institutes of Health Research’s Institute of Circulatory and Respiratory Health (CIHR-ICRH) and the Canadian Lung Association.
Early Career Researcher Award in Asthma
Dr. Zihang Lu
Asthma phenotypes, risk factors and the implications for future
management in Canadian children
In preschool, defining asthma is challenging due to a lack of objective measures along with a heavy reliance on a non-specific symptom of wheeze and a diverse clinical course reflected by remission and relapse. Earlier research shows that asthma is likely caused by several different pathways that are influenced by genetic and environmental factors. We believe these disparate pathways reflect different types of asthma and we aim to identify these pathways in early life using objective methods. To do this, we will use two research data platforms, namely the CHILD Cohort Study and the Canadian Urban Environmental Health Research Consortium. The first aim is to define distinct asthma phenotypes by applying data-driven methods to asthma traits (e.g. wheeze, atopy, body mass index), and to determine whether these phenotypes are different in males and females. The second aim is to determine early-life risk genetic and environmental factors associated with these distinct phenotypes. This study will address several knowledge gaps in our understanding of early life asthma phenotypes and the influences of genetic and environmental exposures on these phenotypes. It will also promote future studies to understand the underlying disease mechanism and provide important evidence to develop disease prevention and management strategies.
This award was jointly funded by Asthma Canada, AstraZeneca Canada, the Canadian Allergy, Asthma and Immunology Foundation (CAAIF), the Canadian Institutes of Health Research’s Institute of Circulatory and Respiratory Health (CIHR-ICRH) and the Canadian Lung Association.
CAAIF Research Fellowship in Type 2 Inflammation
Supported by Sanofi Canada
Dr. Jasmine Barra
Elucidating the mechanism of action of IL-5 as a promoter of IFN
production and NK activation
Allergic asthma is a life-threatening disease. When asthmatic individuals get the flu, caused by viral infection, their airways become heavily inflamed and obstruct with mucus, potentially triggering an asthma attack. To find new treatments to help asthmatic patients deal with viral infections, we focus on one special cell type, the mast cell.
Mast cells are immune sentinel cells, critical for effective response to many pathogens, including viruses. Mast cells recruit immune cells, called natural killer (NK) cells, to the site of infection. NK cells are important because they kill the cells infected by the virus, reducing inflammation. Both recruitment and killing ability of NK cells are boosted by interferons, an important class of chemical messengers. A recent discovery from our Lab showed that, during viral infection, mast cells exposed to interleukin-5 produce greater amounts of interferons, suggesting they could improve antiviral response. Interleukin-5 is a type 2 cytokine, a molecule found elevated in allergic diseases and the target of most common therapies to control asthma.
We propose to investigate how interleukin-5 increases the production of interferons in mast cells. Results from our study will indicate how to promote interferon production during antiviral responses, with important benefits for patients with asthma.
CAAIF Research Fellowship in Type 2 Inflammation
Supported by Sanofi Canada
Dr. Kyle Burrows
Commensal protozoan driven remodeling of lung immunity
Asthma remains a major global health burden that can affect all social classes. The broad range in vulnerability and severity of asthma across populations suggests that there are still unknown risk factors associated with this disease. The gut microbiota, the collection of all microbes living within our intestines, plays an essential role in balancing immune responses and is known to regulate immune cells in the lung via host-microbiota interactions across the ‘gut–lung axis’. Our group has identified a new intestinal protozoan microbe, Tritrichomonas musculis (T.mu), that can shape the local gut immune system. Interestingly, T.mu can also alter immune cell function along the gut-lung axis and bias the lung toward an inflammatory state as well as exacerbate disease following induction of an experimental model of asthma. However, the interactions between the gut and lung immune cells that promote this inflammation are not known. My proposal aims to characterize the changes in immune cell organization within the lungs of mice carrying T.mu in order to uncover how T.mu driven signals across the gut-lung axis can promote lung inflammation. Overall, our results will reveal how T.mu, as an environmental risk factor, can influence the development of asthma.
CAAIF Research Fellowship in Immunology
Supported by Takeda Canda
Dr. Anikó Malik
Investigations of B cells in common variable immune deficiency and autoimmunity
The immune system is a complex network of white blood cells and proteins known as cytokines. Specific antibodies produced by the immune cells defend the body against infection. Immune system dysfunction can lead to repeated, potentially fatal infections (immunodeficiency) and chronic inflammation when the immune system attacks the body’s own tissues (autoimmunity). Common Variable Immune Deficiency (CVID), the most common type, causes a halt in the development of specific blood cells (B-cells), which normally produce protective antibodies. In some patients, it is caused by a genetic mutation; however, in the majority of patients, the cause of poor antibody production is unknown, and the disorder can manifest at any age, including in older adults. Even with the best care, these patients are vulnerable to autoimmunity, which shortens their lives and lower their quality of life. We are investigating the cause of decreased antibody production and how impaired B-cell function leads to autoimmunity. Understanding the basis of dysregulated antibody synthesis should help not only with CVID treatment, but also with the treatment of many chronic inflammatory disorders caused by autoantibodies, such as lupus, arthritis, multiple sclerosis, and others. Mechanism-based therapies should improve patients’ quality of life while reducing the healthcare system’s burden.
CAAIF-Miravo Healthcare Research Grant in Allergic Rhnitis or Urticaria
Dr. Jörg Fritz
Treating allergic rhinitis by blockade of triacylglyceride synthesis
The type 2 immune response is critical for host defense against parasites, wound healing and body metabolism. However, dysregulation of type 2 immunity causes immunopathological conditions, including allergic rhinitis, asthma, atopic dermatitis and anaphylaxis, atopic diseases that also have been referred to as type 2 immunopathologies. Thus, a balanced type 2 immune response must be achieved to mount effective protection against pathogens while avoiding detrimental diseases.
Recent clinical evidence demonstrates that elevated levels of the alarmin interleukin (IL)-33 and group 2 innate lymphoid cells (ILC2) have been found in patients with allergic rhinitis and have been suggested to be key in driving disease. To define novel drug targets for treatment we analyzed molecular signatures leading to dysregulated type 2 immune responses and identified an enzyme involved in triacylglyceride (TAG) lipid metabolism, diacylglycerol acyltransferase 2 (DGAT2), to be central to drive disease. In this study we will test of whether pharmacological inhibitors of DGAT2 (currently used in clinical trials for the treatment of steatosis) and dampen pulmonary allergic immunity and rhinitis. These experiments will allow us to judge of whether repurposing DGAT2 inhibitors should be considered as a promising potential novel therapeutic approach for the treatment of allergic rhinitis.
CAAIF Top 10 Challenge Food Allergy Research Grant
Dr. Bruce Mazer
Processing and characterizing peanuts for a safer and more efficacious substrate for desensitization of peanut allergy
Peanut allergy is extremely common, affecting nearly 1 in every 100 children in Canada and the USA. Recent advances in treatment have emerged in the form of oral immunotherapy (OIT), a controlled process whereby patients are fed progressively larger quantities of peanuts with the goal of building tolerance. However, current OIT protocols do not lead to complete tolerance, and patients still have a significant risk of allergic reactions throughout treatment. Thus, there exists a critical need for a safer and more effective way to treat peanut-allergic patients.
We hypothesize that high-pressure and temperature autoclaving can reduce peanut allergenicity by decreasing the quantity of intact allergenic proteins relative to roasted peanuts. We will determine the optimal autoclaving conditions needed to strike a critical balance between breaking down the peanut enough so that it is safer to consume than roasted peanuts, while simultaneously leaving enough allergen intact so it can effectively build up a tolerance.
For the thousands of individuals and their families suffering from peanut allergy across the globe currently forced to abide by strict avoidance diets, this transformative work could lead to a novel OIT treatment that enables improved or complete tolerance to peanuts, significantly improving their quality of life.
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Graduate Student Award in Asthma
Living (Darlene) Dai
Mining the infant gut microbiota to predict and prevent asthma: data from the CHILD Cohort Study
Asthma is a potentially life-threatening condition that is, unfortunately, the most common chronic disease of childhood, affecting 1 in 7 Canadian children. While treatments can help manage symptoms, there are no curative therapies, which often leads to life-long burdens for diagnosed children. Predicting which children are at-risk of developing asthma and preventing the onset of this disease are therefore key to reducing its burden.
Our research group, and others around the world, have linked the development of asthma to an imbalance in the beneficial community of resident bacteria, called the microbiota, that colonize the guts of infants. This discovery presents a unique opportunity to: (i) identify populations of bacteria that when present in early life in the gut can predict risk of future disease; and (ii) understand these bacteria and use this knowledge to develop preventative strategies based on modifying the composition of the community of bacteria living in the infant gut.
In this research program we will use powerful new genetic sequencing technologies that can profile an infant’s entire microbiome from stool samples to identify functional microorganisms and predict which children will go on to develop asthma. More broadly, our research will guide the development of safe ways to replace missing healthy microbes to prevent asthma from developing in the first place.
This award was jointly funded by Asthma Canada, the Canadian Allergy, Asthma and Immunology Foundation (CAAIF) and the Canadian Institutes of Health Research’s Institute of Circulatory and Respiratory Health (CIHR-ICRH).
Graduate Student Awards in Asthma
Harkiran Kooner
Are CT Mucus Plugs disrupted following two years of Benralizumab treatment in severe, eosinophilic asthma?
Severe, eosinophilic asthma is characterized by airway inflammation and luminal obstruction that occurs as a result of eosinophils in the airways. These patients often report frequent exacerbations and reduced quality-of-life, despite treatment with high-dose medication. Airway mucus plug formation can be encouraged by mucin-eosinophil interactions in the airways and the associated symptoms and airway obstruction are not easily reversed using commonly prescribed asthma therapies. Benralizumab, an interleukin-5 biologic therapy, reduces airway eosinophilia. Thus, this research will investigate whether the elimination of airway eosinophils by benralizumab will alter the presence of mucus plugs, quantified via CT imaging, in the airways of asthma patients after two years of treatment. Based on previously published work, we hypothesize that severe asthma patients with a greater number of mucus plugs prior to treatment will have a greater improvement in quality-of-life and asthma control following benralizumab as a result of the disruption of mucus plugs in their airways. Confirmation of this concept using CT imaging immediately prior to and following two years of therapy will provide the foundation necessary for precision-medicine to target mucus occlusions in patients with poorly-controlled, eosinophilic asthma who do not find relief with traditional asthma therapies. Therefore, this project can identify patients with asthma whom would benefit most from biologic treatment, leading to significantly improved quality-of-life and asthma control in this subset of severe asthma patients.
This award was jointly funded by Asthma Canada, the Canadian Allergy, Asthma and Immunology Foundation (CAAIF) and the Canadian Institutes of Health Research’s Institute of Circulatory and Respiratory Health (CIHR-ICRH).
Graduate Student Award in Asthma
Fang Fang Li
Uncovering viral determinants of asthma development by serological profiling
Worldwide prevalence of asthma has been increasing over the last decade, with higher rates recently observed in industrialized countries. The current leading theory best explaining the worldwide disparity is the hygiene hypothesis, which suggests that exposures to microorganisms during early childhood are essential to preventing immune-related conditions such as asthma by school-age. Supporting the hygiene hypothesis, several studies have demonstrated a protective effect against allergies and asthma in those exposed to Epstein-Barr virus, a common respiratory virus, in their childhood. However, recent research has also demonstrated that other common respiratory viruses, such as human rhinovirus and respiratory syncytial virus, can instead increase the risk of asthma development, thus challenging the hygiene hypothesis. Alongside recent work implicating viral gastroenteritis as another potential risk factor for asthma, we believe that all viral infections could potentially influence the risk of asthma development by school-age, though the direction is virus-dependent. This project aims to link together the complex relationships between asthma and viral infections in young Canadians using Canada’s largest birth cohort, the Canadian Healthy Infant Longitudinal Development (CHILD) study. By uncovering the combinations of viral infections influencing asthma outcome, we can direct new avenues of asthma research and ultimately design better strategies for the prevention and treatment of asthma.
This award was jointly funded by Asthma Canada, the Canadian Allergy, Asthma and Immunology Foundation (CAAIF) and the Canadian Institutes of Health Research’s Institute of Circulatory and Respiratory Health (CIHR-ICRH).
Graduate Student Award in Asthma
Courtney Marshall
Sex-related differences in immunomodulation of airway inflammation by Innate Defence Regulator (IDR) peptides
Asthma is the most common chronic respiratory disease affecting nearly 3 million Canadians including children. Around 15% patients do not respond to available steroid therapies and represent the major burden of asthma accounting for annual healthcare costs of $2B. Also, common steroid therapies can increase the risk of lung infections, which can make asthma worse. New therapies are urgently needed that can alleviate steroid-unresponsive disease without compromising the ability to resolve infections.
There is a clear sex bias in asthma, for example adult females experience greater disease severity and are more likely to develop steroid-resistance, compared to males. These sex-related differences are largely ignored during drug development. Effective development of new treatments must consider the differences in disease and response to therapy between females and males.
This study focuses on new molecules known as innate defence regulator (IDR) peptides, which can control both inflammation and infection. We have shown that IDR peptides improve breathing capacity in an animal model of asthma, and control cellular processes linked to steroid unresponsiveness. This project aims to develop IDR peptides as a new therapy for asthma, by examining the effects in both females and males concurrently. This research will directly support the development of a new IDR peptide-based therapy for asthma, by taking into consideration how the treatment affects females compared to males. It is entirely possible that we will need to develop sex-specific treatment protocols to provide the most efficient care for asthma sufferers.
This award was jointly funded by Asthma Canada, the Canadian Allergy, Asthma and Immunology Foundation (CAAIF) and the Canadian Institutes of Health Research’s Institute of Circulatory (CIHR-ICRH).
Graduate Student Award in Asthma
Christiane Whetstone
Effects of inhaled allergen on eosinophil phenotypes in blood and airways of patients with allergic asthma.
Heightened numbers of eosinophils, eosinophilia, is a hallmark of allergic asthma which often develops during childhood and can be severe during childhood and into adulthood. Biologics targeting the IL-5 pathway, such as mepolizumab and benralizumab, almost completely deplete eosinophils from circulation, however these therapies only partially deplete these cells from the tissue, suggesting tissue eosinophils are less dependent on IL-5 for their survival. Furthermore, anti-IL-5 therapies have varied success at reducing overall asthma severity and symptoms, and this could be due, in part, to eosinophils that remain in tissue. Recent studies report two distinct populations of eosinophils in the human lung; steady state eosinophils (rEOS) and inflammatory eosinophils (iEOS), however it is not understood if the frequency of these eosinophil phenotypes shift during response to an allergic trigger, or whether they have separate and/or overlapping functions. The proposed project aims to identify and enumerate distinct eosinophil phenotypes in circulation and airways to understand their function in asthma. Examining changes in rEOS and iEOS frequency and functionality after an inhaled allergic challenge will allow study of the trafficking and kinetics of eosinophil sub-populations in blood and airways. Our research laboratory has been at the forefront of studying allergic eosinophilic inflammation using whole lung inhaled allergic challenges in mild allergic asthmatics to model the cellular processes that take place during controlled allergic exposures. Using this model to determine cytokine profiles of each distinct eosinophil phenotype will allow us to further understand eosinophil phenotypes and their functions in response to allergen provocation.
This award was jointly funded by Asthma Canada, the Canadian Allergy, Asthma and Immunology Foundation (CAAIF) and the Canadian Institutes of Health Research’s Institute of Circulatory (CIHR-ICRH).
Graduate Student Award in Asthma
Vincent Dandenault
Application of Bayesian networks to multi-omics data to improve the diagnosis of asthma in preschoolers
Preschoolers are two to three times more likely than other age groups to present to the emergency room with asthma-like symptoms. However, they currently cannot be reliably diagnosed as having asthma. Children under the age of 5 cannot undertake a fair spirometry test which is the medical instrument used for this diagnosis. Moreover, given that more than half of children with persistent asthma begin the course of the disease before the age of three years and that deficits in pulmonary function can be established in early wheezer, waiting for diagnosis and management in preschool children can have important implications for disease progression and long-term morbidity. Therefore, our goal is to use machine learning techniques to uncover biomarkers and key physiological pathways that are similar in preschool children and school-aged children confirmed to have asthma. In other words, our goal is to compare children who are likely to have asthma, but cannot be confirmed by spirometry, with children who are confirmed to be asthmatic. We then hope to find similarities that will serve as biomarkers. Indeed, our hypothesis, which could have great potential diagnostic value, is based on the idea that, in the case of asthma, similar physiological pathways represent similar disease processes. We are therefore going to analyse different biological samples, such as blood, breath or saliva, in children, which contain biomarkers allowing the identification of different pathological processes. Specifically, our research will analyze clinical and biological biomarker data from 282 preschoolers and children with asthma symptoms. In other words, we hope to find target indicators in the preschool child group that predict asthma status in the diagnosed child group.
This award was jointly funded by Asthma Canada, the Canadian Allergy, Asthma and Immunology Foundation (CAAIF) and the Canadian Institutes of Health Research’s Institute of Circulatory (CIHR-ICRH).
Graduate Student Award in Asthma
Tony Guo
Characterization of the airway epithelial repair process in late-onset asthma following mechanical, viral, and particulate matter injury of the epithelium
The epithelium, which is the tissue lining our airways, functions as a barrier against irritants and pathogens in the environment such as smoke and viruses. When the epithelium is damaged, it must rapidly repair itself to sustain its normal function. In asthma, the epithelium has a higher sensitivity to environmental stresses which reduces its ability to maintain this barrier and repair when damaged. With more allergens passing through this defective barrier, this contributes to the hallmarks of the asthma such as excessive inflammation and mucus production. Therefore, restoring the integrity of the epithelium and its repair process is important in improving symptoms and disease control for patients living with asthma.
Unfortunately, how these repair processes are altered in late-onset asthma is not well understood. This type of asthma occurs wherein patients first present with the disease in adult, is associated with worsened lung function, and which requires different methods to manage the disease. Risk factors such as sex and obesity, are related to the occurrence of late-onset asthma. However, little is known about how these factors change the function of the airway epithelium and alter the repair process.
Using cell cultures grown from samples obtained from healthy and late-onset asthma patients, this project will measure the extent and rate of repair and the type and concentration of inflammatory molecules released when these cultures are wounded. These measurements may be dependent on the donor patient’s disease severity, sex, age, or other demographic variables. This project will further the understanding of how airway epithelial repair processes are altered by risk factors associated with late-onset asthma.
This award was jointly funded by Asthma Canada, the Canadian Allergy, Asthma and Immunology Foundation (CAAIF) and the Canadian Institutes of Health Research’s Institute of Circulatory (CIHR-ICRH).
Graduate Student Award in Asthma
Nadia Suray Tan
Aberrant lymphocytes and airway autoimmunity: Connecting severe asthma and EGPA pathology
Asthma is a chronic respiratory disease that affects nearly 3.8 million Canadians, with eosinophils, a type of white blood cells, primarily underlying its pathology. Therefore gluococorticosteroids are the cornerstone therapy, and yet a subset remains symptomatic with unresolved inflammation. Our group have detected autoantibodies in the asthmatic airways further associated with severity and suboptimal treatment response. Autoantibodies develop as a misfiring of the immune system where it mistakenly attacks normal healthy cells, leading to tissue damage, more inflammation, and eventually an autoimmune disease. This phenomenon is caused by loss of self-tolerance, where the immune cells are activated by products of tissue damage and the inability of the regulatory immune cells to limit the self-reactivities. The situation often arises where there is ongoing unresolved inflammation, such as the asthmatic airways. That said, both asthma and eosinophils being closely associated with “allergic disease” is thought distantly from autoimmunity. Of interest, Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a rare, life-threatening autoimmune disorder which affect 2.4-6.8 cases per million annually. Asthma and high blood eosinophils are two of the key hallmarks and diagnosis criteria of EGPA. Approximately 40% of EGPA patients have blood anti-neutrophil cytoplasmic antibodies (ANCA). In the past, we have shown EGPA patients marked with severe asthma and airway eosinophilia, have ANCA present in the airway irrespective of their blood ANCA status. Asthma in EGPA is generally severe, require daily oral corticosteroids for disease maintenance, and precedes the onset of the systemic manifestation by several years. Thus, both severe asthma and EGPA patients have local airway autoimmunity. Our overarching goal is to investigate a common underlying pathology that predisposes a subset of severe asthmatics to develop EGPA.
This award was jointly funded by Asthma Canada, the Canadian Allergy, Asthma and Immunology Foundation (CAAIF) and the Canadian Institutes of Health Research’s Institute of Circulatory (CIHR-ICRH).