Research Programs

WordArt of common research themes and diseases studied at the Meakins-Christie LaboratoriesRespiratory Research Programs

Research investigations are focused upon four important respiratory health challenges: chronic airways diseaselung injury and infection, neuromuscular dysfunction in respiratory diseases, and sleep-disordered breathing. The Meakins-Christie Laboratories has a long history of interdisciplinary collaboration, and many members have overlapping interests in more than one of the above research areas. Thus, our researchers study topics that are relevant to a wide range of respiratory diseases including: asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary infections (e.g., chronic bacterial infections with Pseudomonas aeruginosa, TB, viruses and fungi), sleep apnea, muscular dystrophies and other myopathies associated with respiratory diseases, pulmonary fibrosis, lung injury, and other rare respiratory disorders.

Ongoing Research Objectives

Current ongoing research objectives include (but are not limited to) the following:

Primary research themes

  1. Chronic Airways Disease Theme: Elucidate pathogenetic mechanisms and develop novel therapeutics for allergic inflammation & airway hyperresponsiveness. Understand the cellular and molecular basis for irritant (including air pollution & cigarette smoke) -induced lung disease, and its relevance to COPD and the Asthma-COPD Overlap Syndrome (ACOS). Ascertain the biological basis for different asthma phenotypes, particularly severe asthma that is resistant to usual therapies.
  2. Lung Injury and Infection Theme: Identify the key molecular effectors of innate and adaptive immunity required for an integrated response to respiratory pathogens such as influenza, TB, and cryptococcus neoformans. Dissect host-pathogen interactions driving chronic infections versus acute infectious pulmonary exacerbations in chronic lung diseases (eg. Pseudomonas in cystic fibrosis). Investigate the molecular underpinnings of beneficial versus pathological responses by different components of lung mucosal immunity. Explore the mechanistic links between cellular metabolism and fibrogenic processes in the lung.
  3. Neuromuscular Dysfunction in Respiratory Diseases Theme: Elucidate mechanisms of muscle atrophy in the diaphragm and limb muscles of patients with chronic pulmonary diseases. Determine how aging influences the development of muscle atrophy and weakness in respiratory patients. Identify mechanisms of respiratory muscle wasting and injury in non-pulmonary conditions (muscular dystrophy, ICU myopathy). Develop novel therapeutic modalities capable of mitigating muscle atrophy and maintaining muscle strength in the above conditions.
  4. Sleep-Disordered Breathing Theme: Investigate effects of intermittent hypoxia on respiratory and peripheral muscle structure, function, inflammation and metabolism.

Meakins Biobanks, Cohorts, and Animal Models

Several biobanks managed by the Meakins are linked to clinical datasets and support translational research efforts, including asthmatic tissues and bronchoscopic biopsies, sputum and nasal epithelial cells from cystic fibrosis patients, diaphragm tissues, and limb muscle biopsies from COPD patients. As a result, the Severe Asthma Program has banked and studied asthmatic tissues for over 15 years and has published extensively on airway inflammation and remodeling. Collaborations with CanCOLD, a large COPD cohort study, enable biomarker discovery and validation to improve COPD diagnosis and management.

In addition, a number of animal models are available at the Meakins, including for the study of allergic rhinitis, asthma (mouse and rat (BN; Fisher/Lewis)), chronic bronchitis & emphysema (smoking mice), pulmonary fibrosis, muscular dystrophy, cystic fibrosis, infection, and mechanical ventilation. A CRISPR Cas9 derived mouse model has been developed to study genetic susceptibility to cryptococcal infection. Hydra and zebrafish models are available to study the evolution of host response to Pseudomonas aeruginosa infection. Finally, collaborations with the Faculty of Veterinary Medicine at the Université de Montréal permit a unique integration of invasive bronchoscopic and large animal physiologic studies using an equine model of asthma.

Meakins Research Achievements

Scanning electron microscopy of a CD4 T-cell (green), isolated from peripheral blood mononuclear cells, making a lymphocyte-derived membrane conduit with airway smooth muscle cells harvested from human lung tissue (brown). (Photo: James Martin Lab)

Scanning electron microscopy of a CD4 T-cell (green), isolated from peripheral blood mononuclear cells, making a lymphocyte-derived membrane conduit with airway smooth muscle cells harvested from human lung tissue (brown). (Photo: James Martin Lab)

From its earliest days, the cross-disciplinary nature of the Meakins has provided the opportunity for bench to bedside (and bedside to bench) translational research. Over 2000 original manuscripts have been published by investigators at the Meakins in high quality peer reviewed journals. In addition, several textbooks as well as over 100 book chapters have been written by our members.

A number of innovative methodologies have been developed to aid in the measurement of lung function and the diagnosis of human lung diseases. Examples include closing volume, mouth occlusion pressure, measurement of diaphragm activity with surface and esophageal electrodes, and the forced oscillation technique. Researchers have established a clinically relevant rat model of extrinsic asthma, provided new applications of the alveolar capsule technique, developed software for 3D reconstruction of cells, and perfected technologies to permit accurate measurements of complex respiratory physiology in the mouse. Several members have demonstrated that inflammatory cells directly regulate smooth muscle cell responses that contribute to asthma pathogenesis. In addition, the roles of various cytokines, receptors, and signalling molecules in airway inflammation, smooth muscle cell proliferation and remodelling have been defined.

New technological developments for studying asthma include the use of microfluidic chambers to measure drug effects on airway smooth muscle mechanics. A unique suite of muscle mechanics equipment  has been developed that includes an in vitro myosin motility assay, a laser trap assay for determining single myosin molecule properties, and a whole muscle mechanics testing apparatus. Furthermore, members have been leaders in understanding peripheral and respiratory skeletal muscle fatigue and dysfunction in respiratory diseases such as COPD. They have been pioneers in the use of gene therapy to treat respiratory muscle disorders, and discovered new mechanisms by which innate immunity drives diaphragm pathology in muscular dystrophy. They have also defined the entity of ventilator-induced diaphragmatic dysfunction (VIDD) and established the existence of upper airway muscle inflammation, injury and denervation in obstructive sleep apnea.

Other investigators at the Meakins have provided insights into novel therapeutic targets for respiratory infections such as influenza, TB, and Pseudomonas aeruginosa, and identified small molecules as antibiotic adjuvants against respiratory pathogens. Research into the use of biomarkers to assess TB treatment response, respiratory exacerbations in cystic fibrosis, COPD risk, oxidative stress, vascular dysfunction, inflammation, and nutritional intervention success in the critically ill has also been advanced by Meakins researchers.

New drugs and biologic agents for therapy of asthma have been developed. Patents have included an antagonist against STAT6 (US Patent 7829528) which modulates allergic airways disease and inflammation during RSV infection; and an antagonist of the 5-lipoxygenase product 5-oxo-ETE (collaboration with Florida Institute of Technology, US Patent 8809382) which blocks tissue infiltration of eosinophils in a model of allergic asthma.

Book: Physiological Basis of Respiratory Disease. Q Hamid, J Shannon, J Martin

Book: Physiological Basis of Respiratory Disease. Q Hamid, J Shannon, J Martin

Molecular mechanisms of airway smooth muscle contraction. AM Lauzon

Molecular mechanisms of airway smooth muscle contraction. AM Lauzon

Cover: Upper airway muscle pathology in sleep apnea. B Petrof and J Kimoff

Cover: Upper airway muscle pathology in sleep apnea. B Petrof and J Kimoff

Cover: Gene transfer to the diaphragm. B Petrof

Cover: Gene transfer to the diaphragm. B Petrof

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Eosinophil chemoattractant lipids. W Powell

Eosinophil chemoattractant lipids. W Powell

Biglycan (red) & alpha-smooth muscle actin (green) in rat airways. Mara Ludwig

Cover: Biglycan (r) & a-smooth muscle actin (g) in rat airways. MS Ludwig

Cover: In vivo transfected muscular dystrophy muscle fibers. B Petrof

Cover: In vivo transfected muscular dystrophy muscle fibers. B Petrof

Cover: Mechanical ventilation effects on human diaphragm muscle fibers. B Petrof

Cover: Mechanical ventilation effects on human diaphragm muscle fibers. B Petrof

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Cover: SM22 expression of asthmatic endobronchial biopsy. AM Lauzon

Cover: SM22 expression of asthmatic endobronchial biopsy. AM Lauzon

J Physiology Feature: CD4+ T cells and airway smooth muscle. AM Lauzon

J Physiology Feature: CD4+ T cells and airway smooth muscle. AM Lauzon

Science Perspectives Feature: Antioxidant strategies to tolerate antibiotics. D Nguyen

Science Perspectives Feature: Antioxidant strategies to tolerate antibiotics. D Nguyen

This Week in Science Feature: Arrest and Tolerate. D Nguyen

This Week in Science Feature: Arrest and Tolerate. D Nguyen

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Cover: Colonies of Pseudomonas aeruginosa from CF airways. D Nguyen

Cover: Colonies of Pseudomonas aeruginosa from CF airways. D Nguyen

J Immunology Top 10% In this Issue: Nurturing Nanotubes. J Martin

J Immunology Top 10% In this Issue: Nurturing Nanotubes. J Martin

Book: New Paradigm of Immunity to TB. M Divangahi (Editor)

Book: New Paradigm of Immunity to TB. M Divangahi (Editor)

International consortium publishes the first Primer on Tuberculosis in Nature Reviews Disease Primers

International consortium publishes the first Disease Primer on TB. M Divangahi

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