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2009-2010

The Lung Association and its medical section, the Ontario Thoracic Society (OTS), work to promote respiratory health through medical research and continuing education. This Research Update provides a brief summary outlining the 13 projects funded by the Lung Association during the 2009-2010 year in Ontario. The OTS relies on experts from across Canada to review the proposals and is responsible for approving the grants and allocating the research budget. OTS also ensures that a research material is distributed into hospitals, clinics and other health care settings. The Lung Association is proud of the class of academic excellence to improve the respiratory health of Canadians.

Research Funded (2009-2010)

Asthma →
Chronic obstructive pulmonary disease (COPD) →
Lung Disease →
Lung Infection →
Research Grant Awards →

 


Asthma

Dr. Sharon Dell, The Hospital for Sick Children
Making the Link between Objective Measures of Airway Disease and Epidemiological Survey Data: Validation of the ISAAC Questionnaire in Toronto School Children

Most of our Canadian statistics about asthma in children come from questionnaires (eg. ISAAC survey) that ask parents to report whether their child has ever had asthma. In contrast, Canadian asthma guidelines emphasize that physicians should use objective measures of airway disease to verify an asthma diagnosis. Public health and other health services programs rely on this data to estimate burden of disease in order to appropriately allocate services. In addition, it might be important to know what kind of asthma a child has in order to determine what treatment the child will respond to and whether or not he/she will outgrow their asthma. To date, no one has actually studied whether parental reported asthma is the same as specialist diagnosed asthma using objective measures of airway disease and what kinds of asthma Canadian children have.

The main objective of this study is to compare the ISAAC asthma case (parental report on questionnaire) to a specialist diagnosis of asthma using objective measures of airway disease outlined in the Canadian Asthma Consensus Guidelines. Secondary objectives include (1) determining how many children with asthma-related symptoms have undiagnosed asthma and (2) describing the type of asthma that Canadian children have.

The recently assembled T-CHEQ cohort, a population-based sample of 5619 Toronto school children, will be used as the sampling frame. Two hundred children will be randomly selected and classified into 3 different groups: reported asthma, asthma-related symptoms without reported asthma and normal controls. Participating children will undergo a number of tests that are objective measures of airway disease, including spirometry (how hard and fast a child can blow), exhaled nitric oxide measurement( measures airway inflammation), methacholine challenge (measures the twitchiness of the airways) and allergy skin testing (measures whether they have atopy or allergy).

This study is a necessary step in order to have a good understanding of the burden of asthma and the interpretation of Canadian asthma studies. It will be the first study of its kind in Canada and will be unique in the world in that data collected from this study will also be linked to health services use through each participant’s health card information and measures of airway inflammation will be obtained in addition to tests of lung function. The outcome of this project is a necessary intermediate step to answering many important lung health questions exploring the relationship between air quality, asthma and respiratory symptoms in childhood.

Dr. Manel Jordana, McMaster University
Role of Eosinophils and IL-13 in Allergic Airway Dysfunction and Remodeling

Allergic asthma is a chronic disease that develops as a consequence of sustained exposure to common aeroallergens. The most important indoor aeroallergen is house dust mite (HDM). A hallmark of allergic asthma is inflammation of the airways. There are different types of cells that define asthmatic inflammation, one is eosinophils and the other lymphocytes of a particular subset called Th2 cells. Both cell types can produce many different molecules that can either damage the airway or perpetuate the inflammatory reaction. Importantly, the sustained presence of inflammation around the airways leads to changes in their structure, a process referred to as remodelling. It is thought that these changes are important because they impair the function of the airway and, hence, contribute to clinical symptoms. Even though we have learned a great deal about these processes, the precise relationship between airway inflammation, remodelling and dysfunction remains to be elucidated.

A prominent hypothesis today is that eosinophils produce a molecule called transforming growth factor ß (TGFß) which through acting on a number of cells in the airway tissue mediates airway remodelling. In stark contrast with this, our laboratory has produced data demonstrating that, in an experimental model of allergic asthma induced by the exposure to HDM, TGFß is not involved in remodelling. Importantly, in this study, TGFß neutralization was not associated with any diminution in airway eosinophilia. Thus, we propose to ask two questions: 1) Do eosinophils contribute to the development of remodelling and/or the decline in airway function in the context of HDM-exposure?, and 2) What molecules, other than TGFß, may drive the development of HDM-induced remodelling? Specifically, is IL-13 (interleukin 13) a major driver of HDM-induced airway remodelling? The reason for focusing on IL-13, a molecule produced by Th2 cells, is that it has been shown to contribute to remodelling in other systems.

To address these questions we will use a model that has been developed and characterized in our laboratory and which involves the exposure for periods of time to HDM. To examine the role of eosinophils we will use two different strategies. One involves the use of mice that are deficient in eosinophils. However, sometimes, genetically deficient mice evolve compensatory mechanisms; hence, we will administer, in other experiments, an antibody that kills eosinophils. The goal is to see whether in these experimental conditions airway remodelling takes place and how the physiological function of the airways is affected. Similarly, we will use deficient mice and neutralizing antibodies to investigate the role of IL-13 in these processes.

As indicated earlier, inflammation, remodelling, and airway dysfunction are connected; however, the exact cellular and molecular mechanisms underlying these relationships still need to be clarified. Indeed, a substantial part of available data provides correlations that may or may not reflect causality. We have a sound experimental system to address these issues. This, along with very powerful reagents and mouse strains place us in a strong position to answer these questions decisively.

We think that understanding the mechanisms underlying key processes in asthma is directly in line with the L.A. mission. In addition, the research proposed has implications in terms of identifying and/or dismissing potential therapeutic targets.

Dr. Renee Labiris, McMaster University
Preclinical Imaging for the Investigation of Inflammation, Remodeling and Intervention in a Rat Model of Allergic Airway Disease

Allergic asthma is a respiratory disease that currently affects millions of people worldwide. It is known that chronic exposure to common allergens, such as house dust mite (HDM), can lead to allergy and asthma in a subset of the population. Exposure to allergen causes inflammation, i.e. the accumulation of immune cells, in some individuals; these cells release a variety of harmful products which may end up altering the structure of the airway, a process called remodelling. Airway remodelling is important because it is thought to be involved in the impairment of lung function seen in asthmatic individuals. To better understand allergic airway disease we employ models in small animals, such as rats, that mimic the processes involved. New technologies are developed to achieve a more thorough understanding of the events associated with allergic disease.

The specific conditions under which a person becomes asthmatic are not known. Our overall goal is to understand how allergic events can lead to asthma. More specifically, and the aim of this project, is the use of three-dimensional imaging techniques, such as computed tomography (CT) and positron emission tomography(PET), to further understand important events associated with this condition, in particular airway inflammation and remodeling. CT scanning is a technology that provides anatomical images based on tissue density. PET scanning provides biological function images using radiopharmaceuticals targeting a specific function, such as remodeling. PET and CT are commonly used in human patients requiring medical diagnosis for a variety of conditions. Employing PETtCT as an experimental tool, we can study the entire structure as well as the function of the lungs in the same individual across time, a feat that is not possible with traditional methods.

This research will be carried out in a rat model of allergic airway disease. The application of PETtCT for the study of allergic changes in the lung first requires understanding the relationship between imaging data and well-known biological measurements. We will move forward by carefully documenting how PETtCT can be used to track the various situations common to asthma. These situations will include: the evolution of airway inflammation in a short term setting, intervention of inflammation by the use of corticosteroids, chronic inflammation and remodeling.

The use of an aeroallergen that is relevant to humans, i.e. HOM, is an important merit of this project and in contrast to other models of allergic disease that employ egg-white protein. In addition, the development of a tool that can evaluate important processes in asthma within a live animal, and can do this repeatedly, is most significant. This will allow long-term studies and collection of data in one animal under several conditions, potentially reducing the number of animals required for study. To our knowledge, this is the first time that PETtCT scanning will be used for the collection of live animal data in an experimental model of allergic disease. This work will provide a tool that will aid in the evaluation of airway inflammation and remodelling in a model of allergic asthma. Since the evaluation of therapeutics and imaging techniques in humans is limited, this work will provide an experimental platform on which to pre-screen future therapeutics and diagnostic techniques. We believe that these goals are fully relevant to the mission of the Lung Association.

Dr. Diane Lougheed, Queen’s University
Clinical Relevance of Abnormal Symptom Perception in Asthma: A prospective cohort study

Poor perception of asthma symptoms may be a risk factor for life-threatening asthma. We have shown individuals with poor perception of the over inflation of the lungs that occurs during an asthma attack are more obese, have a larger resting inspiratory capacity (more ‘room to breathe’), are less anxious and report having been admitted to intensive care units more commonly than individuals with normal symptom perception. The objective of this study is to determine whether over and under recognition of asthma symptoms is linked to poor patient outcomes such as acute attacks and visits to hospital emergency departments.

A group of asthma subjects (~125) will be tested to determine whether they have poor, normal or increased perception of lung over inflation during a simulated asthma attack. The will be followed for 2 years. The risk of adverse outcomes such as severe attacks needing hospitalization will be determined. This will be the first study to attempt to determine the clinical importance of abnormal perception of lung inflation during asthma attacks. The findings may reduce risk factors for near-fatal and fatal asthma attacks, which in turn may help decrease asthma deaths. Poor and over perception of asthma symptoms may be risk factors for life-threatening asthma. This research is directly in line with the Lung Association’s mission as it aims to improve the lung health and outcomes of individuals with asthma, by advancing our understanding of factors linked to asthma morbidity and mortality.

Dr. Grace Parraga, London Health Sciences Centre
The Relationship between Hyperpolarized Helium-3 Magnetic Resonance Ventilation Heterogeneity and Airway Hyper-responsiveness in Asthma

Asthma is a chronic disease of the lungs that leads to serious breathing problems including shortness of breath and coughing, hospitalization and in some cases death. According to the World Health Organization, asthma is a serious public health problem with over 100 million sufferers worldwide. According to Statistics Canada, 8.4% of Canadians older than 12 years of age have a diagnosis of asthma (2000-2001) and moreover, asthma is affects at least 12% of Canadian children. While there are treatments that can control symptoms of asthma, there is no cure, so there is an urgent need to develop new ways to measure asthma changes for the testing of potential new treatments that target the disease itself, not just the symptoms.

The objective of this proposed research project is to use a novel imaging magnetic resonance imaging (MRI) tool and an MR visible inhaled gas to provide evidence of the underlying lung changes in asthma as well as the relationship between these lung changes and asthma symptoms, lung inflammation and the response to an asthma trigger test (methacholine challenge). We will study 25 patients between 18 and 50 years of age with no smoking history, all with a diagnosis of asthma within the last 5 years and currently under treatment by an asthma specialist. During a single five hour visit to our lung imaging center, we will measure 1) lung function and volumes using standard tests, 2) inflammation – using a breath analysis test, 3) breathlessness – using a standard scale, and finally, 4) image patients lungs using 3He MRI and CT. This will take about 2 hours in total and then all patients will undergo a methacholine trigger test with MR imaging at the end of the test and after inhaling from a ventolin “puffer”. We will quantify imaging and other lung function measurements and symptoms to understand the relationship between the new and established measurements of asthma.

Robarts is the only clinical research facility for hyperpolarized gas lung MR imaging research in Canada and one of only a small handful of such facilities that exist in the world. Hyperpolarized helium-3 (3He) magnetic resonance imaging (MRI) has recently emerged as a research approach for the non-invasive measurement of lung structure and function, including conduction of gas through airways and into airspaces. Preliminary studies suggest that 3He MRI is ideally suited for clinical research, because it is safe for patients and provides information not available using other methods.

This project outlines the largest effort yet to understand the relationship between lung structural and functional images and other established measurements of asthma lung function, symptoms, inflammation and response to a well-established trigger test. We have already developed image analysis tools for the sensitive, specific and precise measurement of in vivo 3He MRI functional and will now apply these to images from 25 asthma patients. The quantitative measurement of 3He MRI and CT images in asthma will provide an understanding of the significant relationships between these and with established lung function measurements. The results will allow us to understand the imaging measurements and whether they can be considered as endpoints for future asthma studies of new potential treatments.

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Chronic Obstructive Lung Injury (COPD)

Dr. Roger Goldstein, West Park Healthcare Centre
Optimizing outcomes gained from pulmonary rehabilitation: the development of a community-based maintenance exercise program for individuals with COPD

Chronic obstructive pulmonary disease (COPD) is a common and costly condition in Canada and in the rest of the world. It is well known that respiratory rehabilitation for patients with COPD can help to improve their exercise tolerance and quality of life. However, after the hospital-based rehabilitation is over, these benefits tend to decline over time. This decline in outcomes is largely because patients discontinue their physical exercise program once they have left the hospital.

The goal of this research project is to develop and implement a supervised exercise program in a community setting for individuals with COPD who have recently completed a respiratory rehabilitation program. We will also aim to determine whether supervised community-based exercise has the potential to maintain benefits gained from respiratory rehabilitation for these patients.

We will form a partnership with a local community recreation centre to develop this program. Fitness instructors from the community centre will be trained about the needs of patients with COPD and the supervised exercise program will contain elements common to respiratory rehabilitation programs in Canada. We will measure participants’ exercise tolerance and quality of life both at the beginning and end of rehabilitation, and following the six-month exercise program. Rate of attendance to the program and patient attitudes towards the program will also be considered.

This project will offer patients a new way to continue exercising in the community with their peers after completing their rehabilitation program. This will be the first research to formally study such a program in Canada. The findings of this proposed work will result in a new strategy to help patients maintain training-related gains made during respiratory rehabilitation, specifically exercise tolerance and quality of life. The information gained from this project will also be used to develop a larger study to determine if a community-based exercise program can help patients with lung disease to maintain their quality of life and exercise capacity up to one year after rehabilitation.

Dr. Denis O’Donnell, Queen’s University
The Effect of Obesity on Dyspnea and Exercise Performance in COPD

The prevalence of both COPD and obesity is increasing dramatically in Canada and “the obese COPD patient” is recognized as an increasingly common clinical presentation. When these serious health problems coexist in patients, there are potentially important physiological and clinical consequences which to-date have received very little scientific scrutiny. The main purpose of this study is to examine the physiological effects of the combination of obesity and COPD on the perception of breathlessness and exercise performance. In particular, we wish to better understand the consistent but “paradoxical” finding of a previously CTS/CLA supported study where we found that the coexistence of obesity and COPD had favourable effects on breathlessness and exercise tolerance, at least when tested during cycle ergometry.

We will compare detailed perceptual (quality and intensity of breathlessness) and physiological responses (breathing pattern, respiratory mechanics and muscle function, lung gas exchange) to both cycle and treadmill exercise in groups of patients with COPD (with similar airway obstruction) with and without obesity (BMI>30 kg/m2). In this way we will determine how the breathing and perceptual responses to both weight-supported (cycle) and weight-bearing (treadmill) are affected by obesity in patients with COPD. This is the first study to carefully probe the physiological interaction of obesity and COPD. We will discover the clinical implications of this combination with respect to symptom perception and activity limitation in obese COPD patients. This study will advance our extensive work on mechanisms of breathlessness in COPD. If we can confirm our recent observation that the reduced lung hyperinflation that accompanies abdominal obesity is an advantage for COPD patient, then the stage is set to develop and test novel interventions to relieve breathlessness that mimic some of the main mechanical effects of obesity (such as abdominal banding) in normal weight patients with COPD.

The CLA and CTS are committed to prevention and optimal management of COPD, a leading cause of death in Canada. Basic physiological research such as that proposed here is urgently needed if we are to improve the management of breathlessness and activity limitation in those who suffer from COPD. This project which is set to advance our understanding of the origin of the dominant symptoms in COPD fits perfectly with the mission statement of the Lung Association.

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Lung Disease

Dr. Kayvan Amjadi, The Ottawa Hospital
Randomized Controlled Trial of Pregabalin for the Treatment of Chronic Cough

Chronic cough is a very common respiratory complaint, accounting for up to 40% of the practice volume in North American outpatient Respirology clinics. Persistent coughing can have a significant effect on the quality of life of sufferers. The objective of this study is to evaluate the effectiveness of pregabalin, a medication used for treatment of seizures and chronic pain, in the treatment of chronic cough.

We will conduct a pilot randomized controlled trial comparing pregabalin to placebo in patients with chronic cough. This is the first study evaluating the effects of pregabalin in the treatment of chronic cough. Additionally, our study will use the validated Leicester Cough Questionnaire as the primary endpoint. With over 30 million physician visits annually in North America, chronic cough is a very common respiratory complaint. Up to 20% of these patients will have a cough that is refractory to standard therapy. Consequently, there is a clear need for novel therapeutic agents in this field. If we are able to demonstrate the effectiveness of pregabalin, this would have a major impact on the therapy of chronic cough and the lung health of Canadians.

Dr. Nancy Ford, Ryerson University
Assessing Lung Morphology in Rodents using Respiratory-gated Micro-computed Tomography

Mechanical ventilation is used clinically to provide oxygen to patients that are unable to breathe, or to assist patients that have difficulties breathing and are unable to get enough oxygen on their own. However, long-term ventilation may cause permanent damage to the lungs. Characterizing how normal, healthy lungs respond to mechanical ventilation will provide information about how the lung structure and function changes and may lead to new techniques for mechanical ventilation in the clinical setting. We aim to understand how different respiratory patterns can cause changes in lung structure and function, such as changes in how lungs inflate and deflate, and how inhaled air spreads inside the lungs, in normal healthy rodents. Breathing patterns that will be studied include:

  1. natural breathing patterns, such as free-breathing in sleeping rodents and free-breathing in hibernating rodents (hibernation mimics a breathing disorder called apnea, which is a series of breaths followed by a long period with no respiration), and
  2. mechanically ventilated breathing patterns, where the rodent is connected to a respirator that will force a known amount of air into the lungs at a defined rate.

In mice and rats, we will obtain 3D x-ray images during different parts of the breathing cycle while they are free-breathing. Each animal will be put onto a respirator and mechanically ventilated and imaged again. Lung structure and function will be measured and compared between the images of each animal. To study the effects of altered breathing patterns, we will take 3D x-ray images of ground squirrels throughout their activity cycle, including periods of activity in the summer months and periods of hibernation in the winter months. During hibernation, the squirrels take a few deep breaths, then no breaths for several minutes, which is similar to clinical symptoms of apnea. Measurements of lung structure and function will be compared throughout the seasonal cycle, corresponding to different naturally occurring breathing patterns in healthy squirrels.

We have created a method to obtain 3D x-ray images during different parts of the breathing cycle in free-breathing mice and rats. Our imaging technique is unique because we use high speed imaging equipment that captures x-ray images from all angles around the animal in under 1 minute; this equipment is only available in 2 locations across Canada. Our technique is also non-invasive, meaning needles or surgery are not required, so there is no damage to the animals during the scan, allowing the same animal to be imaged many times over a period of weeks or months. Currently, the high-speed micro-CT scanner at the Robarts Research Institute in London, ON is the only location world-wide that can perform these techniques for imaging free-breathing mice and rats.

The proposed research will provide information about how mechanical ventilation affects the lungs – how the lungs inflate and deflate, how inhaled air spreads inside the lungs, etc. – of healthy rodents. By understanding the differences between forced ventilation and free-breathing in healthy normal lungs, we will be able to predict how diseased lungs will respond under the same mechanical ventilation procedures. We will also study changes in lung structure and function during periods of altered breathing similar to apnea. We expect the results of the proposed work may impact clinical procedures for patients on assisted respiration during surgery or while comatose or in clinical hypothermia.

Dr. Luke Janssen, McMaster University
Calcium-Signaling and Gene Expression in Human Pulmonary Fibroblasts

One of the hallmarks of chronic lung diseases is the destruction of matrix, a structure critically important for the gas exchange function of the lungs. Fibroblasts are cells embedded in the matrix. In diseases such as fibrosis or chronic asthma there are too many of these cells in too much matrix, in emphysema there are not enough or they are distributed in an abnormal pattern. Beside the ability to produce matrix, fibroblasts are able to contract and influence tissue stiffness. Changes in ion concentration including calcium have marked effects on fibroblast function. We want to investigate if these ion alterations have a direct influence on the tissue strain and matrix composition in the lung, and if correcting abnormal calcium levels in or around fibroblasts have a beneficial effect on chronic lung disease.

Fibroblasts are the cells in the lungs which can either destroy lung tissue or create scar tissue which interferes with normal lung function. We would like to better understand how they work. We know that they have to express genes, and that gene expression in other cells is affected by a chemical change: a change in the concentration of calcium inside the cells. We also know that fibroblasts demonstrate very interesting calcium responses when they are stimulated. So we want to look at the relationship between changes in calcium inside the cells and gene expression.

We get human lung fibroblasts from lung tissues removed in operations. We can then pull out the fibroblasts and study them using our special microscopes (confocal, laser-illuminated, fluorimetric microscope) in order to see the changes in calcium under various experimental conditions. We can also look at how they express genes. We will therefore look at that gene expression under conditions in which calcium levels are changed. Very few people have looked at calcium responses in fibroblasts, and nobody world-wide has looked at the possibility that gene expression in fibroblasts might be affected by those calcium responses. Fibroblasts play a very important role in both asthma and COPD: they cause changes in the structure of the lungs which lead to many of the consequences of those diseases. A better understanding of how they “work” could open the door to new drugs which would control what they do, and therefore help treat those diseases.

Dr. Andrew Leask, University of Western Ontario
Protein kinase C epsilon: a novel target for anti-fibrotic drug intervention?

Scleroderma is a scarring disease affecting the skin and internal organs. Patients with scleroderma often die due to scarring of the lungs. There is no treatment for lung scarring in scleroderma. The objective of my research program is to solve this problem. We want to test whether a particular protein called protein kinase c epsilon is necessary for scarring of the lung. Our long-term aim is to determine if drugs targeting protein kinase c epsilon might be used to prevent or cure scarring of the lung in diseases such as scleroderma.

We will test whether loss of protein kinase c epsilon causes resistance to scarring. Our approach is entirely unique as this idea has not been proposed or tested before. A major problem for health care in Canada is lung scarring, including in scleroderma. There is no treatment currently available for this problem. The overall objective of my research program is to determine how scarring occurs and hence how to treat this process. The outcome of this project will be a first step in determining if drugs blocking the action of protein kinase C epsilon might be used as therapies for lung fibrosis, including in scleroderma.

Dr. Peter John McPherson, University of Toronto
The role of Bclaf1 (Bcl-2 associated factor 1) in lung development

Various molecular ‘circuits’ control the growth and development of various cell types in the development of lungs during gestation. Imbalances in these molecular ‘circuits’, particularly those that control the growth of smooth muscle in the lung, have been linked to several lung diseases including bronchopulmonary dysplasia, asthma and interstitial fibrosis. This application proposes to examine Bclaf1, a gene we have identified as a regulator of smooth muscle lineage development in the neonatal lung of mice. We will use mice deficient in Bclaf1 to determine how Bclaf1 directs the regulation of smooth muscle development in the lung. Mice deficient in Bclaf1 show an excess of smooth muscle cells in the lung just before birth. We will use various techniques to determine whether the excess smooth muscle cells appear because these cells acquire an increased capacity to grow and divide, or whether they have lost the ability to undergo programmed cell death. We have found that Bclaf1 protein interacts with two other proteins known as 9G8 and TAP. Both proteins impact the regulation of genes by regulating pre-mRNA splicing and transport. We will examine whether Bclaf1 affects the ability of 9G8 and TAP to properly regulate these processes. The ability of Bclaf1 to regulate pre-mRNA splicing and transport may help to explain the importance of Bclaf1 in controlling smooth muscle cell development in lungs. Our laboratory is unique in having the availability of mice deficient in Bclaf1 to study its role in development.

Several pulmonary diseases have been found to have defects in the growth or loss of smooth muscle. Understanding how smooth muscle development is regulated in the lung may help us understand how this control is lost in lung diseases. The identification and characterization of genes such as Bclaf1 that control lung development may provide new opportunities for designing new and improved therapeutic strategies to treat pulmonary disease.

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Lung Infection

Dr. Zhou Xing, McMaster University
Role of immunoreceptor DAP12 in negative regulation of immune activation and immunopathology during respiratory influenza viral infection

This research proposal deals with lung flu virus infection. Acute lung flu infection is caused by influenza virus and it continues to be an important cause of sickness or even death particularly in children, elderly people and those with chronic disease in North America and elsewhere in the world. Like many other lung viral infectious diseases, often the clinical symptoms and tissue injury in the lung are caused by imbalanced or uncontrolled immune responses that attempt to contain or clear the virus from the lung. Much still remains to be understood as to why this is happening.

Our current research project was designed to investigate the mechanisms that help the host to control the immune response that may otherwise damage the lung tissue in the course of acute lung flu virus infection. More specifically, we will study the role of a recently identified molecule or protein called DAP12 (DNAX activating protein of 12kDa), that is on the surface of some of our immune cells. Unfortunately little is known about whether and how this molecule may play a role in host defense against lung flu virus infection. In the past half year, we have obtained the evidence that this molecule is important in this process as the laboratory animals that do not have this molecule in their immune system become severely ill and some of them die of virus infection within 9 days of time but their illness is not due to enhanced viral infection. In fact, we have found that these animals could control viral infection as well as the wild type animals expressing this molecule. However, the lungs of these animals suffer a much greater extent of inflammation and tissue injury. We have further found that these animals have greater numbers of innate immune or inflammatory cells in their lungs and elsewhere. Based on these initial observations, our current project will continue to dissect in more detail the role of DAP12 in regulation of immune responses and lung pathology in the course of lung flu virus infection and its mechanisms. In addition to examining the expression of DAP12 and associated receptors in the lung during acute flu virus infection, we will examine the activation state of infiltrating inflammatory cells and find out which of these cells are responsible for severe and sometimes lethal lung tissue injury. The unique aspect of our project is that we are the 1st to have identified the critical role of this molecule, DAP12, in determining the level of lung inflammation and tissue injury during flu infection. Therefore, our research project will generate new knowledge to help understand why some people die of acute lung flu infection and may eventually lead to the development of novel therapeutic strategies to save more lives.

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Research Grant Awards

All grants are awarded based on ranking by national peer review process conducted by the Canadian Thoracic Society. Budget requests totaling $2,211,479, funding was approved for 13 of the 31 applications to be distributed in descending order of priority, based on their calculated national percentile ranking.

Approved and Recommended for Funding (Alphabetically)
Amount Awarded
Dr. Kayvan Amjadi, Ottawa Hospital
Randomized Controlled Trial of Pregabalin for the Treatment of Chronic Cough
$38,696
Dr. Sharon Dell, Hospital for Sick Children
Making the Link Between Objective Measures of Airway Disease and Epidemiological Survey Data: Validation of the ISAAC Questionnaire in Toronto School Children
$50,000
Dr. Nancy Ford, Ryerson University
Mandibular Movement During Sleep
$36,486
Dr. Roger Goldstein, West Park Healthcare/University of Toronto
Optimizing outcomes gained from pulmonary rehabilitation: the development of a Community based maintenance exercise program for individuals with COPD
$46,061
Dr. Luke Janssen, McMaster University
Calcium-Signaling and Gene Expression in Human Pulmonary Fibroblasts
$50,000
Dr. Manel Jordana, McMaster University
Role of Eosinophils and IL-13 in Allergic Airway Dysfunction and Remodeling
$49,000
Dr. Renee Labiris, McMaster University
Preclinical Imaging for the Investigation of Inflammation, Remodeling and Intervention in a Rat Model of Allergic Airway Disease
$49,834
Dr. Andrew Leask, University of Western Ontario**
Protein kinase C epsilon: a novel target for anti-fibrotic drug intervention?
$45,000
Dr. Diane Lougheed, Queen’s University
Clinical Relevance of Abnormal Symptom Perception in Asthma: A prospective cohort study
$49,628
Dr. John Peter McPherson, University of Toronto
The Role of Bclaf1 Bcl-2 associated factor 1) in lung development
$50,000
Dr. Denis O’Donnell, Queen’s University
The Effect of Obesity on Dyspnea and Exercise Performance in COPD
$49,550
Dr. Grace Parraga, Imaging Research Laboratories, Robarts Research Institute
The relationship between Hyperpolarized Helium-3 Magnetic Resonance Ventilation Heterogeneity and Airway Hyper-responsiveness in Asthma
$49,575
Dr. Zhou Xing, McMaster University
Role of immunoreceptor DAP12 in negative regulation of immune activation and immunopathology during respiratory influenza viral infection
$50,000

 

** OLA/OTS Breathe New Life Award: The funds for the “Breathe New Life Award” are partly raised by the OTS members through the Top It Up! For Respiratory Research fund. This fund enhances the nationally reviewed and acclaimed Grant-in-Aid research competition and funds grants above and beyond the normal value of the GIA budget provided by the Ontario Lung Association (OLA).

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