Grace Parraga, PhD
"Do not wait to strike till the iron is hot;
but make it hot by striking."
- William B. Sprague (1795-1876)
Scientist, CIHR New Investigator
Robarts Research Institute
Professor and Graduate Chair
Department of Medical Biophysics
Departments of Oncology, Medical Imaging, Graduate Program in Biomedical Engineering
The University of Western Ontario
Research Interests and Projects
Welcome to our Research program!
If you are a potential postdoctoral, graduate, or undergraduate trainee, please feel free to download our recent publications by clicking the Papers button - many of these are summarized below.
Understanding how we breathe to change health outcomesWe are fascinated by the interactions of lung growth and development with lung aging and disease. The lungs are central to homeostasis and to life so that without optimal lung structure and function, all other physiological systems in humans are compromised and eventually fail. Paradoxically, lung abnormalities are expressed “silently” until disease mechanisms are well-established or irreversible because fundamentally, the respiratory system is over-engineered for day to day tasks. This makes detection and a deep understanding of lung disease and its mechanisms, extremely challenging.
We think that lung function can be understood and explained by exploring the interplay between the airways and airspaces as they grow, develop and adapt in response to the external environment. Research in our laboratory is directed towards a detailed understanding of lung structure and function, with an emphasis on the development of human medical imaging tools.
A variety of biophysical techniques are used in the Parraga laboratory, with a major emphasis on high resolution magnetic resonance imaging measurements made in vivo in children and adults and exploring their relationship with lung physiology. Ongoing projects are focussed on answering fundamental questions about lung health, such as:
Can early disease detection, using imaging, improve patient outcomes like quality of life and survival?
Do reversible lung functional abnormalities become irreversible over time? (Does asthma lead to COPD?)
Can we use imaging measurements to change/improve clinical treatment decisions?
Does lung disease start in the airways or airspaces?
Are there underlying disease mechanisms that link cardiovascular vessel and lung structure-function abnormalities?
Are currently available methods for monitoring and diagnosing lung diseases sufficient?
Can regional imaging measures of lung structure and function provide insight regarding disease initiation and progression?
Structure-Function Imaging of AsthmaFunded by CIHR.
Institutions: Dalhousie University, Western University, Robarts Research Institute, McMaster University
Co-Investigators: Dr. Param Nair, Dr. Geoff Maksym, Dr. David McCormack, Dr. Chris Licskai
Asthma is commonly diagnosed and characterized by the measurement of the forced expiratory volume in 1s (FEV1) - a simple and inexpensive spirometry measurement of airflow obstruction. As a result, current and newly developed asthma therapies are mainly directed towards and evaluated by improvements in FEV1. Unfortunately, FEV1 measurements do not always capture peripheral airway dysfunction or provide information relevant to the heterogeneity of airway dysfunction which may have profound consequences for the work of breathing and gas exchange. We also now realize that the specific airway abnormalities that may be directly responsible for asthma symptoms and exacerbations are most likely heterogeneously distributed in the lung and this information cannot be easily evaluated using global airflow volume measurements. Because of this, we think that methods for measuring and mapping regional asthma structure-function will provide the critical breakthroughs required for the next generation of asthma therapies.
We previously showed that broncho-constrictive response to exercise and methacholine is heterogeneously localized, and we have recent evidence that for individual patients, the same lung regions that appear persistently abnormal are also involved in functional responses to asthma triggers. We also recently showed that asthma functional abnormalities can be mapped to specific airways and these can be modeled in silico to generate the regional and global effects observed in patients. Unfortunately, despite these recent findings and decades of asthma research, current clinical tools cannot provide a non-invasive way to: 1) differentiate between diseased and normal airways in individual asthma subjects, 2) identify regional structural and functional targets for asthma therapy, and, 3) regionally measure regional asthma changes over time or in response to therapy. In other words, currently there is no way to measure regional asthma abnormalities making it difficult if not impossible to develop and test regional asthma treatments. By developing regional asthma structure-function measurements and maps there is the potential to guide regional therapy to specific airway abnormalities, generating a paradigm shift for asthma treatment and care.
Medical imaging has played a very limited role in advancing asthma research, and the numerous advantages of imaging have not been translated to clinical use. This is a critical translational gap that has had a highly negative impact on asthma patient care; we think this can be addressed by the development of novel 129Xenon (129Xe) gas contrast magnetic resonance imaging (MRI) analysis methods dedicated to the study of asthma. In this project we optimize and apply these tools, providing critical technological steps required for translational pulmonary functional MRI for asthma research and image-guidance.
The overarching goal of our research program is to develop and validate methods required to provide a detailed in vivo understanding of the underlying structure-function relationships in asthma through the identification, quantification and evaluation of imaging measurements. Over 5 years, we will acquire 129Xe MRI in asthmatics in whom we seek to characterize and probe the relationship between lung structure and function using imaging as follows:
Thoracic Imaging Network of Canada (TIN Can)Funded by CIHR.
Institutions: University of British Columbia, Western University, Robarts Research Institute
Co-Investigators: Dr. James Hogg, Dr. Don Sin, Dr. Harvey Coxson, Dr. John Mayo, Dr. Stephen Lam, Dr. Giles Santyr, Dr. Aaron Fenster, Dr. David MCormack
Currently, COPD clinical care and research depends upon lung function measurements as the gold standard markers of disease progression and severity. Unfortunately, these measurements provide no information about COPD pathological phenotypes and these are furthermore insensitive to important functional and structural changes that occur over time. Therefore, the key anticipated value of this CIHR Team relates to integrated interdisciplinary research that develops and validates highly predictive hybrid imaging maps and models of the COPD lung, to improve our fundamental understanding of COPD phenotypes, leading to new intermediate endpoints and biomarkers that will translate to new and better patient treatments, management and outcomes. In summary, the value-added of this team approach is related to the translation of research tools and results from COPD tissue ex vivo analysis to in vivo patient imaging studies. In Theme A, we identify and quantify ex vivo lung tissue structural measurements from resected tissue from COPD patients and these results will generate "ground truth" to generate a validation platform for MDCT, MRI, OCT, and spectroscopy measurements developed in vivo in the same patients in Themes B and C. Our deliverables for the program and team include:
Longitudinal COPD Phenotyping using Hyperpolarized 3He MRIFunded by CIHR.
Institutions: University of British Columbia, Western University, Robarts Research Institute
Co-Investigators: Dr. Harvey Coxson, Dr. David McCormack, Dr. Giles Santyr
The development of chronic lung disease related to tobacco smoking, the use of biomass fuels and inhalation of environmental toxins, known as Chronic Obstructive Pulmonary Disease (COPD) affects at least one million Canadians and 600 million people worldwide. It is currently the fourth leading cause of death worldwide and continues to grow in prevalence and mortality rates. It is directly responsible for 10,000 deaths and 100,000 hospitalizations each year in Canada, costing over $5 billion in direct and indirect costs. Despite the staggering societal burden of COPD and decades of active research, therapeutic breakthroughs have not occurred, largely because there is: 1) an incomplete understanding of COPD pathogenesis, 2) inadequate patient phenotyping, and, 3) a scarcity of tools that can sensitively and precisely track disease changes. These limitations are critical considerations when new therapies are evaluated in clinical trials because the surrogate endpoints currently in use are poor surrogates for long-term health outcomes - the ultimate target of new treatments. In response to these serious limitations, non-invasive in vivo imaging techniques have been proposed as promising solutions because of their potential to provide new remedial intermediate markers or phenotypes that directly quantify lung pathologic and functional changes. Accordingly, the focus of this research proposal is the quantification and validation of such in vivo COPD phenotypes.
We think that 3He MRI provides a complementary and alternative method for evaluating COPD and may be superior to CT because it allows simultaneous visualization of airway and airspace structure and function at high spatial and temporal resolution, without x-ray radiation risk. We hypothesize that imaging measurements can be used to determine the relative contributions of airway obstruction and emphysema in individual patients and furthermore provide a better way to stratify patients based upon underlying pathological changes. The stratification or differential phenotyping of COPD patients based upon different underlying pathologies has the potential to have a profound effect on patient management because the treatments required are likely very different.
The goal of this research is to provide a detailed in vivo understanding of the underlying pathophysiology of COPD, through the identification and validation of in vivo imaging intermediate endpoints. As a first step, we will develop image analysis tools for the sensitive, specific and precise measurement of both airways and airspace changes, providing for the first time, an in vivo window on these complex underlying COPD pathologies. These tools will provide a way to measure lung pathological and functional changes longitudinally and stratify patients based upon pathologies that are mechanistically-related, but very different. Quantitative in vivo phenotypes also provide new COPD intermediate endpoints for interventional and genetic studies, identified by NIH as a critical research gap that needs to be addressed. Accordingly, we propose over the next 3 years to quantify and validate 3He MRI and CT imaging phenotypes of COPD within three specific aims.
Specific Aim 1: Identify, quantify and provide histological validation of disease structural and functional phenotypes derived from 3He MR and CT of subjects with GOLD stage 2 and 3 COPD.
Imaging the Healthy Aging LungFunded by CIHR.
Institutions: Western University, Robarts Research Institute
Co-Investigators: Dr. David McCormack, Dr. Nigel Paterson, Dr. Roya Etemad-Rezai, Dr. Giles Santyr
Respiratory changes that accompany aging such as global lung function decreases and regional structural alterations result in increased breathlessness or higher risk of respiratory illness and decreased exercise tolerance, all of which result in decreased quality of life. Despite decades of active research, as well as the staggering and growing societal burden of the effects of diminished respiratory function in the elderly, little is known about how to differentiate "usual aging" representing the effects of aging mixed with the potentially negative lifestyle and environmental factors, from "unusual aging" reflecting not only a lack of apparent disease but physiological performance that is not significantly different from healthy young adults. Moreover, currently there are no tools that can be used to predict those who might be at risk of accelerated aging.
In this regard, we recently were the first to report the unexpected 3He magnetic resonance imaging (MRI) finding that healthy elderly never-smokers with apparently normal lung function, exhibited lung imaging changes that were not significantly different from age-matched ex-smokers with Global Obstructive Lung Disease (GOLD) stage II chronic obstructive pulmonary disease (COPD). These surprising imaging findings suggested that significant and unexpected lung changes were occurring in healthy elderly never-smokers (with apparently age-normalized lung function), providing important clues about the aging lung and identifying the (previously unrecognized) potential for lung imaging to provide sensitive measurements of aging.
Our central hypothesis is that lung MRI provides in vivo phenotypes or intermediate candidate markers of lung morphology and function that can be used to quantify healthy respiratory aging and to differentiate between "usual" and "unusual" aging lung. We also hypothesize that imaging measurements will show significant associations with established measurements of functional capacity and exercise-induced dyspnea and will respond to bronchodilatory intervention. A fundamental understanding of healthy aging lung structure and function has the potential to guide the development of novel strategies to improve functional declines, evaluate predisposition to accelerated lung aging and identify environmental and other risk factors. As a first step towards this goal, we are evaluating novel image acquisition and analysis tools already developed in our lab for the sensitive, specific and precise measurement of lung changes, providing for the first time, an in vivo window on these complex underlying age-related changes in elderly never-smokers. We are quantifying MRI measurements in 180 healthy elderly never-smokers within four specific aims as follows:
Specific Aim 1: Quantify and compare in vivo lung structural and functional 3He and 1H MRI measurements at baseline and three years later and determine the significant relationships between these and pulmonary function measurements, lung volumes, and functional capacity;
Lung Micromechanical Modeling using Magnetic Resonance ImagingFunded by NSERC.
The traditional view of lung function and mechanics has been derived from simple 2 compartment models and measurements developed using pressure and flow measurements at the mouth or tubes fixed to the end of the trachea of excised lungs. Despite the importance of these traditional approaches, it has unfortunately, not yet been possible to incorporate regional lung information to better develop lung models of function and mechanics. To directly address this decades-old problem, we are incorporating lung imaging measurements of airway and airspace structure and function into existing models of lung micromechanics and developing new models and testing these using regional functional imaging information. The overarching objective of this research is to develop new ways to use lung tissue and airway functional and structural quantitative measurements derived from 3He and 129Xe MRI in obstructive lung disease like asthma and COPD as well as healthy volunteers to generate and develop robust mathematical models of pulmonary biomechanics. This approach provides a way to incorporate, test and validate regional in vivo imaging measurements to generate novel micromechanical models of the lung.
Imaging Biomarkers of Carotid AtherosclerosisFunded by Pfizer, CIHR and HSFO.
Institutions: Western University, Robarts Research Institute
Co-Investigators: Dr. David Spence, Dr. Aaron Fenster
The lab currently has three main projects in carotid atherosclerosis research that have been undertaken over the last 5 years: 1) development and validation of new measurements of carotid atherosclerosis that include volumetric evaluation of arterial wall and plaque, 2) ECG-gating of 3DUS measurements of carotid atherosclerosis to improve precision of measurements in young subjects (such as pre-menopausal females with rheumatoid arthritis), and, 3) quantitative mapping of carotid atherosclerosis in longitudinal studies. All studies are approved by Health Canada and the local research ethics board. We have been awarded funding for these projects from the the Lawson Health Research Institute (Internal Research Fund), Pfizer, Virtual Scopics, Wyeth, F. Hoffman- La Roche, and as co-PI from CIHR, HSFO and CIHR Proof of Principle Grants. Currently 2 graduate students (and 3 graduated MSc students) have worked on these projects as well as a research technician and 3 expert observers who perform the carotid segmentation tasks. In this area of research, and since 2006, my lab has published 14 peer-reviewed manuscripts in this research area as well as 4 book chapters.
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