I study the genetics and pathophysiology of obstructive lung disease in the hope of finding novel mechanisms that will lead to new diagnostic and therapeutic approaches.
Asthma, Emphysema, Genetics, Lung Disease, Chronic Obstructive Pulmonary Disease
- My most important contributions have been to enhance our understanding of the pathophysiology of obstructive airway disease, particularly asthma and Chronic Obstructive Airway Disease (COPD). Beginning in 1977 I began to collect phenotypic data and the resected lung specimens from smokers who had lung tissue resected for peripheral lung lesions. This extensive registry, which now contains over 6000 samples has been an invaluable resource for phenotypic, morphologic, and more recently, molecular biologic & genetic studies. I have published > 45 papers related to the registry.
- In 1986 with Dr. Rodrigo Moreno, I published a paper entitled: The Mechanics of Airway Narrowing. This paper, which has been cited more than 700 times, has served as the basis for a series of more than 60 papers describing in vivo and in vitro function, morphometric data, and models designed to examine the mechanism(s) by which airways narrow excessively in lung disease. This work led to a renewed appreciation of the inflammation and airway remodeling which characterizes asthma and COPD.
- Working in collaboration with Drs. Schellenberg and Seow, I have studied the mechanical properties, pharmacological responsiveness and ultrastructural organization of human and animal airway smooth muscle (ASM). We have focused on airway smooth muscle shortening in addition to force generation and we were the first to study the plastic behavior of airway smooth muscle and its influence on the responsiveness of airways to tidal breathing and deep inspiration. More than 30 publications have resulted from this area of research. This work has contributed to the renewed interest in the role of ASM in airway narrowing.
- We have used lungs frozen at the time of resection to do genetic, immunohistochemical and molecular biology studies. For example we have studied the protein and mRNA expression of growth factors, cytokines and their receptors in lungs from patients with asthma and COPD as well as the degrees of lung epithelial cell apoptosis and its relationship to the expression of Fas and Fas L. We have completed a genome-wide examination of genes differentially expressed in the lungs of patients with varying degrees of COPD and are presently analyzing the relationship between genome-wide gene expression and genome wide genotypes in over 1,200 lung tissues to discover expression quantitative traits.
- Working with Drs Muller, Coxson and Hogg, I have contributed to the development of novel techniques to assess lung emphysema, cystic fibrosis and airway remodeling using High Resolution Computed Tomographic scanning.
- I have contributed to the study of the genetics of asthma and COPD. In the mid 1990’s, with Andrew Sandford I wrote two State of the Art review articles designed to introduce the pulmonary community to the enormous potential offered by the molecular genetics revolution. Since then I have published more than 45 papers and chapters related to the genetics of asthma and COPD. I have developed collaborations with investigators in the NIH funded Lung Health Study to study genetic determinants of COPD and with Canadian and European collaborators have conducted the largest Genome Wide Association studies of asthma to date. I am the PI for one of 10 international centres in a COPD genetics network in which we have recruited 1300 families who have COPD. I was the PI on a large CIHR IHRT grant to investigate gene-environment interaction in Heart and Lung disease and I am involved in consortia GWAS for Asthma, COPD and Cystic fibrosis. I was the genetics leader of the Genes and Environment group which is part of the AllerGen National Centers of Excellence program.
- I was the original PI of a CIHR/Heart and Stroke Foundation funded Strategic Training Initiative in Health Research program call IMPACT (Integrated and Mentored Pulmonary and Cardiovascular Training) which has been renewed for another 6 year term.
- With 3 co-authors I have published a number of editions of Diagnosis of Diseases of the Chest a widely used four volume text on the diagnosis lung disease.
1. Zhang J, Daley D, Akhabir L, Stefanowicz D, Chan-Yeung M, Becker AB, Laprise C, Paré PD, Sandford AJ: Lack of association of TIM3 polymorphisms and allergic phenotypes, BMC Med Genet 2009, 10:62
2. Bosse Y, Chin LY, Paré PD, Seow CY. Chronic Activation in Shortened Airway Smooth Muscle: A Synergistic Combination Underlying Airway Hyperresponsiveness? Am J Respir Cell Mol Biol. 2010;42(3):341-8.
3. Chin LY, Bossé Y, Jiao Y, Solomon D, Hackett TL, Paré PD, Seow CY. Human airway smooth muscle is structurally and mechanically similar to that of other species. Eur Respir J. 2010;36(1):170-177.
4. Bosse Y, Solomon D, Chin LY, Lian K, Paré PD, Seow CY. Increase in Passive Stiffness at Reduced Airway Smooth Muscle Length: Potential Impact on Airway Responsiveness Am J Physiol Lung Cell Mol Physiol 2010;298(3):L277-87.
5. Gosselink JV, Hayashi S, Elliott WM, Xing L, Chan B, Yang L, Wright C, Sin D, Paré PD, Pierce JA, Pierce RA, Patterson A, Cooper J, Hogg JC. Differential Expression of Tissue Repair Genes in the Pathogenesis of COPD. Am J Respir Crit Care Med. 2010;181(12):1329-35.
6. Kicic A, Hallstrand TS, Sutanto EN, Stevens PT, Kobor MS, Taplin C, Paré PD, Beyer RP, Stick SM, Knight DA. Decreased Fibronectin Production Significantly Contributes to Dysregulated Repair of Asthmatic Epithelium. Am J Respir Crit Care Med. 2010;181(9):889-898.
7. Behzad AR, Walker DC, Abraham T, McDonough J, Mahmudi-Azer S, Chu F, Shaheen F, Hogg JC, Paré PD. Localization of DNA and RNA in eosinophil secretory granules. Int Arch Allergy Immunol. 2010;152(1):12-27.
8. Hersh CP, Pillai SG, Zhu G, Lomas DA, Bakke P, Gulsvik A, Demeo DL, Klanderman BJ, Lazarus R, Litonjua AA, Sparrow D, Reilly JJ, Agusti A, Calverley PM, Donner CF, Levy RD, Make BJ, Paré PD, Rennard SI, Vestbo J, Wouters EF, Scholand MB, Coon H, Hoidal J, Silverman EK. Multi-Study Fine Mapping of Chromosome 2q Identifies XRCC5 as a COPD Susceptibility Gene. Am J Respir Crit Care Med. 2010;182(5):605-13.
9. Sorheim IC, Bakke P, Gulsvik A, Pillai SG, Johannessen A, Gaarder PI, Campbell EJ, Agusti A, Calverley PM, Donner CF, Make BJ, Rennard SI, Vestbo J, Wouters EF, Paré PD, Levy RD, Coxson HO, Lomas DA, Hersh CP, Silverman EK. Alpha-1 antitrypsin PI MZ heterozygosity is associated with airflow obstruction in two large cohorts. Chest 2010;138(5):1125-32.
10. Zhang J, Herrera AM, Paré PD, Seow CY. Dense-body aggregates as plastic structures supporting tension in smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2010;299(5):L631-8.
11. Raqeeb A, Solomon D, Paré PD, Seow CY.Length oscillation mimicking periodic individual deep inspirations during tidal breathing attenuates force recovery and adaptation in airway smooth muscle. J Appl Physiol. 2010 Sep 9.
12. Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, von Mutius E,Farrall M, Lathrop M, Cookson WO;GABRIEL consortium. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med. 2010;363(13):1211-1221.
13. Wright FA, Strug LJ, Doshi VK, Commander CW, Blackman SM, Sun L, Berthiaume Y, Cutler D, Cojocaru A, Collaco JM, Corey M, Dorfman R, Goddard K, Green D, Kent JW Jr, Lange EM, Lee S, Li W, Luo J, Mayhew GM, Naughton KM, Pace RG, Paré PD et al. Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. Nat Genet. 2011 May 22. [Epub ahead of print]
14. Syyong HT, Raqeeb A, Paré PD, Seow CY. Time course of isotonic shortening and the underlying contraction mechanism in airway smooth muscle. J Appl Physiol. 2011 Jun 2. [Epub ahead of print]
- Michael Smith Distinguished Researcher
- Jacob Churg Distinguished Investigator