(Carleton University, Ottawa, ON, Canada)
Chair, Smooth Muscle Research Group
Canada Research Chair & AIHS Senior Scholar
Associate Professor, Biochemistry & Mol. Biology
Room GAA20, HRIC Building
3280 Hospital Drive NW,
Calgary, AB, T2N 4Z6
Phone Office: (403) 210-8433
Phone Lab: (403) 220-6636
Fax: (403) 270-2211
Current research efforts are focused on four main topics:
(1) Zipper-interacting Protein Kinase (ZIPK) and the Control of Smooth Muscle Contraction
ZIPK is a Ser/Thr-protein kinase that has been linked to the regulation of a number of processes, including cellular motility, programmed cell death and smooth muscle cell contraction. Interaction of ZIPK with different scaffolding and substrate pools have important functional implications regarding its ability to regulate vascular smooth muscle contractile capacity. Primarily, we are investigating the molecular mechanisms whereby ZIPK contributes to smooth muscle contractility through the regulation of myosin phosphatase phosphorylation. Our studies address the molecular and structural elements of ZIPK and apply this foundational information to examine the contribution of the kinase to vascular smooth muscle contractility in health and disease. Additional objectives are aimed at identifying specific ZIPK inhibitors as well as identifying ZIPK substrates through complementary chemical-genetics strategies.
(2) Smoothelin-like 1 (aka SMTNL1 or CHASM) and Smooth Muscle Contraction.
We recently discovered a novel smooth muscle protein that promotes an exaggerated vascular contractile phenotype. The SMTNL1/CHASM protein is part of an adaptive contractile response of smooth muscle to various perterbations, including exercise, aging and pregnancy. Our research examines the molecular and structural elements governing the association of SMTNL1/CHASM with important muscle proteins (i.e., calmodulin and tropomyosin) as well as the physiological signfiicance of these interactions on vascular smooth muscle biology.
(3) Intestinal Motile Dysfunction Associated with Gastrointestinal Inflammation.
Inflammatory mediators have a profound effect on smooth muscle contraction and hence intestinal motility. We are examining the molecular events underlying phenotypic changes in contractile responses of the intestine to pathological inflammation. The underlying mechanisms for the regulation pathophysiology of smooth muscle function in Crohn's disease and ulcerative colitis is being examined. Research is determining how signaling mechanisms that control smooth muscle contractility are compromised in these inflammatory bowel diseases.
(4) The Pathogenesis of Clostridium difficile-associated Colitis
Clostridium difficile (Cdf) is the leading cause of hospital-acquired infectious diarrhea, and recent epidemics in Canada have placed a heavy econoic and social burden on health care provision. We are investigating innate mechanisms that contribute to disease progression. For example, hypoxia-inducible factor (HIF-1) plays a vital innate protective role in Cdf-associated colitis. Furthermore, our investigations are also examining the molecular mechanisms that underlie GI contractile changes with Cdf infection. An understanding of signaling pathways affected by Cdf to induce contractile dysfunction (i.e., toxic megacolon) may lead to targeted therapy and improved clinical outcomes.
Archives of Biochemistry and Biophysics Special Issue "Protein Kinases and phosphatases: regulators of motile systems." Link to Special Issue
M.P. Walsh, J.A. MacDonald (2011) Guest Editors' Introduction. Arch Biochem Biophys 510(2): 73-75.
M.E. Grassie, L.D. Moffat, M.P. Walsh, J.A. MacDonald (2011) The myosin phosphatase targeting protein (MYPT) family: A regulated mechanism for achieving substrate specificity of the catalytic subunit of protein phosphatase type 1. Arch Biochem Biophys 510(2): 147-159.
L.P. Schenck, S.A. Hirota, C.L. Hirota, P. Boasquevisque, S.E. Tulk, Y. Li, A. Wadhwani, C.T.A. Doktorchik, W.K. MacNaughton, P.L. Beck, J.A. MacDonald. (2013) Attenuation of Clostridium difficile toxin-induced damage to epithelial barrier by ecto-5'-nucleotidase (CD73) and adenosine receptor signaling. Neurogastroenterol Motil [Epub ahead of print]
G.D. Armstrong, D.R. Pillai, T.J. Louie, J.A. MacDonald, P.L. Beck. (2013) A potential new tool for managing Clostridium difficile infection. J Infect Dis [Epub ahead of print]
J.A. MacDonald, L.D. Moffat, A. Al-Ghabkari, C. Sutherland, M.P. Walsh (2013) Prostate-apoptosis response-4 phosphorylation in vascular smooth muscle. Arch Biochem Biophys [Epub ahead of print]
N.A. Bracey, P.L. Beck, D.A. Muruve, S.A. Hirota, J. Guo, H. Jabagi, J.R. Wright, J.A. MacDonald, J.P. Lees-Miller, D. Roach, L.M. Semeniuk, H.J. Duff. (2013) The Nlrp3 inflammasome promotes myocardial dysfunction in structural cardiomyopathy through IL-1beta. Exp Physiol 98(2): 462-72.
S.A. Hirota, V. Iablokov, S.E. Tulk, L.P. Schenck, H. Becker, J. Nguyen, S. Al Bashir, T.C. Dindle, A. Laing, J. Liu, Y. Li, J. Bolstad, G.L. Mulvey, G.D. Armstrong, W.K. MacNaughton, D.A. Muruve, J.A. MacDonald*, P.L. Beck*. (2012) Intrarectal instillation of Clostridium difficile toxin A triggers colonic inflammation and tissue damage: development of a novel and efficient mouse model of Clostridium difficile toxin exposure. Infect Immun 80: 4474-84. (* co-senior PIs)
M.E. Grassie, C. Sutherland, A. Ulke-Lemee, M. Chappellaz, E. Kiss, M.P. Walsh, J.A. MacDonald. (2012) Cross-talk between Rho-associated kinase and cyclic nucleotide-dependent kinase signaling pathways in the regulation of smooth muscle myosin light chain phosphatase. J Biol Chem 287: 36356-69.
B.D. Gulbransen, M. Bashashati, S.A. Hirota, X. Gui, J.A. Roberts, J.A. MacDonald, D.A. Muruve, D.M. McKay, P.L. Beck, G.M. Mawe, R.J. Tompson, K.A. Sharkey. (2012) Activation of neuronal P2X7 receptor-pannexin-1 mediates death of enteric neurons during colitis. Nature Medicine 18(4): 600-4.
J.A. MacDonald, E.I. Butler, H. Ishida, A. Ulke-Lemee, M. Chappellaz, S.E. Tulk, J.K. Chik, H.J. Vogel (2012) The intrinsically disordered N-terminus of CHASM interacts with the calponin homology domain to enable tropomyosin binding. Biochemistry 51(13): 2694-705.
J.A. Hirota, S.A. Hirota, S.M. Warner, D. Stefanowicz, F. Shaheen, P.L. Beck, J.A. MacDonald, T.L. Hackett, D.D. Sin, S. Van Eede, D.A. Knight (2012) The airway epithelium nucleotide-binding domain and leucine-rich repeat protein 3 inflammasome is activated by urban particulate matter. J Allergy Clin Immunol 129(4): 1116-1125.e6.
E. Ihara, M. Chappellaz, S.R. Turner, J.A. MacDonald (2012) The contribution of protein kinase C and CPI-17 signaling pathways to hypercontractility in murine experimental colitis. Neurogastroenterol Motil 24(1): e15-26. PubMed Link
L.D. Moffat, S.B. Brown, M.E. Grassie, A. Ulke-Lemee, L.M. Williamson, M.P. Walsh, J.A. MacDonald (2011) Chemical genetics of zipper-interacting protein kinase reveal myosin light chain as a bona fide substrate in permeabilized arterial smooth muscle. J Biol Chem 286(42): 36978-91. PubMed Link
E. Ihara, H. Akiho, K. Nakamura, S.R. Turner, J.A. MacDonald (2011) MAPKs represent novel therapeutic targets for gastrointestinal motility disorders. World J Gastroint Pathophysiol 2(2): 19-25. PubMed Link
J. Fichna, M. Dicay, S.A. Hirota, D. Traboulsi, J.A. MacDonald, A. Janecka, P.L. Beck, J.K. Zjawiony, W.K. MacNaughton, M.A. Storr (2011) Differential effects of salvinorin A on endotosin-induced hypermotility and neurogenic ion transport in mouse ileum. Neurogastroenterol Motil 23(6):583-e212. PubMed Link
A. Ulke-Lemee, S.R. Turner, S.H. Mughal, M.A. Borman, R.J. Winkfein, J.A. MacDonald (2011) Mapping and functional characterization of the murine Smoothelin-like 1 promoter. BMC Mol Biol 12: 10-21. PubMed Link
S.A. Hirota, J. Ng, A. Lueng, M. Khajah, K. Parhar, Y. Li, M.S. Potentier, D.-M. McCafferty, K.P. Rioux, V. Lam, S. Ghosh, R.J. Xavier, S.P. Colgan, J. Tschopp, D. Muruve, J.A. MacDonald, P.L. Beck (2010) The NLRP3 inflammasome plays a key role in the regulation of intestinal homeostasis. Inflamm Bowel Dis 17(6): 1359-72. PubMed Link
A. Ulke-Lemee, H. Ishida, M.A. Borman, A. Valderrama, H.J. Vogel, J.A. MacDonald (2010) Tropomyosin binding properties of the CHASM protein are dependent upon its calponin homology domain. FEBS Lett 584: 3311-3316. PubMed Link
J. Ng, S.A. Hirota, O. GroB, Y. Li, A. Ulke-Lemee, M.S. Potentier, L.P. Schenck, A. Vilaysane, M.E. Seamone, H. Feng, G.D. Armstrong, J. Tschopp, J.A. MacDonald, D.A. Muruve, P.L. Beck (2010) Clostridium difficile toxin-induced inflammation and intestinal injury are mediated by the inflammasome. Gastroenterology 139(2): 542-552. PubMed Link
S.A. Hirota, K. Fines, J. Ng, D. Traboulsi, J. Lee, E. Ihara, Y. Li, W.G. Willmore, D. Chung, M.M. Scully, T. Louie, S. Medlicott, M. Lejeune, K. Chadee, G.D. Armstrong, S.P. Colgan, D.A. Muruve, J.A. MacDonald*, P.L. Beck* (2010) Hypoxia-inducible factor signaling provides protection in Clostridium difficile-induced intestinal injury. Gastroenterology 139(1): 259-269. (* co-senior PIs) PubMed Link
P.L. Beck, E. Ihara, S. A. Hirota, J.A. MacDonald, D. Meng, N.N. Nanthakumar, D.K. Podolsky, R.J. Xavier (2010) Exploring the interplay of barrier function and leukocyte recruitment in intestinal inflammation by targeting fucosyltransferase VII and trefoil factor 3. Am J Physiol Gastrointest Liv Physiol 299: G43-53. PubMed Link
M.J. Johnson, A. Wang, M.E. Catarino, L. Ball, V.C. Phan, J.A. MacDonald, D.M. McKay (2010) Extracts of the rat tapeworm, Hymenolepis diminuta, suppress macrophage activation in vitro and alleviate chemically-induced colitis in mice. Infect Immun 78: 1364-1375. PubMed Link
A. Ulke-Lemee, J.A. MacDonald (2010) Opportunities to target specific contractile abnormalities with smooth muscle protein kinase inhibitors. Pharmaceuticals 3: 1739-1760. Pharmaceuticals Link
Alberta Innovates- Health Solutions
Canada Research Chair Program (Link to CRC Profile).
Canadian Institutes of Health Research
Canadian Association of Gastroenterology
Heart & Stroke Foundation of Alberta, NWT and Nunavut
Research Technician / Laboratory Manager