We aim to elucidate mechanisms that control airway smooth muscle cell phenotype and function, and identify how these contribute the role of airway myocytes and fibroblasts in the pathogenesis of bronchial asthma. Different projects investigate RhoA signaling in gene expression, mechanical strain and of TGFbeta effects of gene transcription and phenotype, and the role of plasma membrane lipid rafts in control of GPCR signaling and myocyte contraction. We also have projects on going that investigate gene expression profiles in lung and blood specimens from patients with COPD. We have established research expertise in several areas including primary cell culture of human and animal airway smooth muscle and fibroblasts, assessment of gene promoter activity, transient expression of signaling proteins using mammalian expression vectors,confocal microscopy, measuring intracellular calcium flux in live cells, applying mechanical strain to cultures cells, detecting and measuring cell-cell coupling using fluorescent imaging techniques and other cell and molecular biology methods.Our current projects include:
- Characterization of human airway wall mesenchymal cell subpopulations, and mechanisms for differential response to asthma-associated mediators such as TGFß
- Role of PI(3) kinase signalling in control of transcription of genes encoding smooth muscle-specific contractile apparatus proteins.
- Dissecting the role of caveolins and caveolae in determining functional coupling and regulation of G-protein coupled receptors in airway smooth muscle cells.
- Determining the role of caveolins in airway responsiveness and allergen-induced airway remodelling and hyperresponsivness.
- Dissecting the role of caveolin proteins in synergism between G-protein coupled receptors and receptor tyrosine kinases in airway smooth muscle cell proliferation
- Characterization of the dystrophin-glycoprotein complex in airway smooth muscle and assessment of its role in mechano-sensing and mechano-transduction.
- Determining signal transduction pathways controlled by laminin-specific receptors in airway smooth muscle cell differentiation and function.
- B.Sc. (4 Year) (Biology), Univ. of Winnipeg, 1983
- M.Sc. (Plant Science), Univ. of Manitoba, 1987
- Ph.D. (Physiology), Univ. of Manitoba, 1996
- Postdoctoral Fellow (Respiratory and Critical Care), Univ. of Chicago, 1996-99
- Assistant Professor (Physiology and Internal Medicine), Univ of Manitoba, 1999-present
- Associate Professor (Physiology and Internal Medicine), Univ of Manitoba, 2004- present
Dr. Halayko is a Principal Mentor of the The Canadian Institutes of Health Research (CIHR) Strategic Training Program in Allergy and Asthma, which offers competitive awards for high quality graduate, post doctoral, and clinical research trainees.
Dr. Halayko also holds a cross appointment in the Department of Medicine, Section of Respiratory Diseases.Research Interests
Our long-term research objective is to elucidate mechanisms that control airway smooth muscle cell phenotype and function, and identify how they contribute the role of airway myocytes in the pathogenesis of bronchial asthma. Airway smooth muscle cells retain a capacity for phenotype plasticity, thus they can regulate airway lumen diameter both acutely, through contraction and through altered contractile responsiveness, and chronically, as key players driving fibro-proliferative and inflammatory features of airway remodelling, including dramatic airway smooth muscle hypertrophy. Our laboratory has been instrumental in developing current paradigms for smooth muscle/mesenchymal cell plasticity in the airways, describing the existence of stable phenotypically distinct mesenchymal cell subpopulations, and identifying molecular mechanisms for their development.
We use cell and molecular biology, and whole animal physiology techniques to investigative molecular mechanisms that mediate altered smooth muscle and airway function in asthma. We have established research expertise in several areas including primary cell culture of human and animal airway myocytes and fibroblasts, flow cytometry techniques to isolate distinct airway myocyte subpopulations, assessment of gene promoter activity, transient expression of signalling proteins using mammalian expression vectors, confocal microscopy, measuring intracellular calcium flux in live cells, applying mechanical strain to cultures cells, detecting and measuring cell-cell coupling using fluorescent imaging techniques, measurement of mouse lung function using whole body plethysmography, and measurement of pharmacological and contractile proper6ties of isolated airway smooth muscle preparations.
- S Watanabe*, A Yamasaki*, K Hashimoto, Y Shigeoka, H Chikumi, Y Hasegawa, T Sumikawa, M Takata, R Okazaki, M Watanabe, T Yokogawa, WT Gerthoffer, AJ Halayko & E Shimizu. Expression of functional leukotriene B4 receptors on human airway smooth muscle cells. J Allergy Clin Immunol 124:59-65 2009 (* equal contribution)
- AJ Halayko & S Ghavami. S100A8/A9: a mediator of severe asthma pathogenesis and morbidity? Can J Physiol Pharmacol, 87:743-755, 2009
- S Ghavami, S Chitayat, M Hashemi, M Eshraghi, WJ Chazin, AJ Halayko & C Kerkhoff. S100A8/A9: a Janus-faced molecule in cancer therapy and tumorgenesis. Eur J Pharmacol. 625:73-83 2009
- R Gosens, HA Baarsma, IH Heijink, AJ Halayko, H Meurs & M Schmidt. De novo synthesis of β-catenin via H-Ras and MEK regulates airway smooth muscle growth. FASEB J 24:757-768, 2010
- S Ghavami, M Eshragi, SR Ande, WJ Chazin, T Klonisch, AJ Halayko, KD McNeill, M Hashemi, C Kerkhoff & M Los. S100A8/A9 induces autophagy and apoptosis via ROS mediated cross-talk between mitochondria and lysosomes that involves BNIP3. Cell Res 20:314-331, 2010
- BGJ Dekkers, IST Bos, R Gosens, AJ Halayko, J Zaagsma & H Meurs. Integrin-blocking peptide RGDS inhibits airway smooth muscle remodeling in a guinea pig model of allergic asthma. Am J Resp Crit Care Med 181:556-65, 2010
- S Ghavami, MM Mutawe, K Hauff, GL Stelmack, D Schaafsma, P Sharma, KD McNeill, T Hynes, SK Kung, H Unruh, T Klonisch, G Hatch, M Los & AJ Halayko. Statin-triggered cell death in primary human lung mesenchymal cells involves p53-PUMA and release of Smac and Omi but not cytochrome C. Biochim Biophys Acta 1803:452-467, 2010
- L Shan NS Redhu, A Saleh, AJ Halayko, J Chakir & A Soussi Gounni. Thymic stromal lymphopoietin receptor-mediated IL-6 and CC/CXC chemokines expression in human airway smooth muscle cells: role of MAPKs (ERK1/2, p38, and JNK) and STAT3 pathways. J Immunol 184:7134-7143, 2010
- P Sharma, S Ghavami, GL Stelmack, KD McNeill, MM Mutawe, T Klonisch, H Unruh & AJ Halayko. β-Dystroglycan binds caveolin-1 in smooth muscle: Functional role in caveolae distribution and Ca2+ release. J Cell Sci 123:3061-3070, 2010
- R Gosens, GL Stelmack, ST Bos, G Dueck, MM Mutawe, D Schaafsma, H Unruh, WT Gerthoffer, J Zaagsma, H Meurs & AJ Halayko. Caveolin-1 is required for contractile phenotype maturation by airway smooth muscle cells. J Cell Mol Med. doi: 10.1111/j.1582-4934.2010.01246.x. [Epub ahead of print] December 30 2010
- DL Milton, AN Schneck, DA Zeich, M Ba, KC Facemyer, AJ Halayko, JE Baker, WT Gerthoffer & CR Cremo. Direct evidence for functional smooth muscle myosin in the 10S self-inhibited monomeric conformation in airway smooth muscle cells. Proc Natl Acad Sci U S A. 108:1421-1426, 2011
- S Ghavami, MM Mutawe, P Sharma, KD McNeill, T Klonisch, H Unruh, M Los & AJ Halayko. Autophagic and apoptotic cell death triggered by mevalonate cascade inhibition in airway mesenchymal cells: a dual role for p53. Revised manuscript submitted to PLoS One J6(1):e16523, 2011
- D Schaafsma, G Dueck, S Ghavami, A Kroeker, K Hauff, FY Xu, KD McNeill, H Unruh, G Hatch & AJ Halayko. The mevalonate cascade as a target to suppress extracellular matrix synthesis by human airway smooth muscle. Am J Respir Cell Mol Biol 44:394-403, 2011
- NS Redhu, A Saleh, AJ Halayko, AS Ali & AS Gounni. Essential role of NF-κB and AP-1 transcription factors in TNFα-induced TSLP expression in human airway smooth muscle cells. Am J Physiol (Lung Cell Mol Physiol) 300:L479-485, 2011
- M Zhu, PY Liu, DI Kasahara, AS Williams, NG Verbout, AJ Halayko, A Fedulov, T Shoji, ES Williams, K Noma, SA Shore & JK Liao. Role of Rho kinase isoforms in murine allergic airway responses. Eur Respir J 38:8418-50 2011
- D Schaafsma, KD McNeill, MM Mutawe, S Ghavami, H Unruh, E Jacques, M Laviolette, J Chakir & AJ Halayko. Simvastatin inhibits TGFβ1-induced fibronectin in human airway fibroblasts. Respir Res 12:113 2011