个人简介

B.Sc. (Bachelor of Science) Ph.D. (Doctor of Philosophy)

研究领域

Genomics Proteomics and Bioinformatics Cell Signalling and Structure

(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.

近期论文

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J.A. MacDonald, C. Sutherland, D.A. Carlson, S. Bhaidani, A. Al-Ghabkari, K. Sward, T.A.J. Haystead, M.P. Walsh. (2016) A small molecule pyrazolo[3,4-D]pyrimidinone inhibitor of zipper-interacting protein kinase suppresses calcium sensitization and contractility of vascular smooth muscle. Mol Pharmacol 89(1): 105-17 (doi:10.1124/mol.115.100529; PMID 26464323). A. Ulke-Lemee, S.R. Turner, J.A. MacDonald. (2015) In situ analysis of smoothelin-like 1 and calmodulin interactions in smooth muscle cells by proximity ligation. J Cell Biochem 116(11): 2667-75 (doi:10.1002/jcb.25215; PMID 25923522). S.E. Tulk, K.C. Liao, D.A. Muruve, P.L. Beck, J.A. MacDonald. (2015) Vitamin D3 metabolites enhance the NLRP3-dependent secretion of IL-1b from human THP-1 monocytic cells. J Cell Biochem May; 116(5): 711-720 (doi:10.1002/jcb.24985; PMID 25639477) J.A. MacDonald. (2015) A tale of two threonines: myosin phosphatase inhibition and Ca2+ sensitization of smooth muscle. J Physiol Feb 1; 593(3): 487-488 (PMID 25774393). E. Ihara, Q. Yu, M. Chappellaz, J.A. MacDonald. (2015) ERK and p38MAPK pathways regulate myosin light chain phosphatase and contribute to Ca2+ sensitization of intestinal smooth muscle contraction. Neurogastroenterol Motil Jan; 27(1): 135-46 (doi:10.1111/nmo.12491; PMID 25557225). A. Ulke-Lemee, H. Ishida, M. Chappellaz, H.J. Vogel, J.A. MacDonald. (2014) Two domains of the smoothelin-like 1 protein bind apo- and calcium-calmodulin independently. Biochim Biophys Acta – Proteins Proteomics Sept; 1844(9): 1580-1590 (doi: 10.1016/j.bbapap.2014.05.011; PMID 24905744). S.R. Turner, J.A. MacDonald. (2014) Novel contributions of the smoothelin-like 1 protein in vascular smooth muscle contraction and its potential involvement in myogenic tone. Microcirculation Apr; 21(3): 249-58 (doi: 10.1111/micc.12108; PMID 24267201) D.A. Carlson, A.S. Franke, D.H. Weitzel, B.L. Speer, P.F. Hughes, L. Hagerty, C.N. Fortner, J.M. Veal, T. E. Barta, B.J. Zieba, A.V. Somlyo, C. Sutherland, J.-T. Deng, M.P. Walsh, J.A. MacDonald, T.A.J. Haystead. (2013) Fluorescence-linked enzyme chemoproteomic strategy for discovery of a potent and selective DAPK1 and ZIPK inhibitor. ACS Chem Biol Dec; 8(12): 2715-23. A. Hansen, L. Alston, S.E. Tulk, L.P. Schenck, M.E. Grassie, A.T. Verrmalla, S. Al-Bashir, F.-P. Gendron, C. Altier, J.A. MacDonald, P.L. Beck, S.A. Hirota. (2013) The P2Y6 receptor mediates Clostridium difficile toxin-induced CXCL8/IL-8 production and intestinal epithelial barrier dysfunction. PLoS One Nov 22; 8(11): e81491. (doi: 10.1471/journal.pone.0081491; PMID 24278446). J.Y. Lee, S.A. Hirota, L.E. Glover, G.D. Armstrong, P.L. Beck, J.A. MacDonald. (2013) Effects of nitric oxide and reactive oxygen species on HIF-1alpha stabilization following Clostridium difficile toxin exposure of the Caco-2 epithelial cell line. Cell Physiol Biochem. Aug 27; 32(2): 417-430. L.P. Schenck, S.A. Hirota, C.L. Hirota, P. Boasquevisque, S.E. Tulk, A. Wadhwani, C. Doktorchik, W.K. MacNaughton, P.L. Beck, J.A. MacDonald. (2013) Attenuation of C. difficile toxin-induced damage to epithelial barrier by ecto-5’-nucleotidase (CD73) and adenosine receptor signaling. Neurogastroent Motil Jun; 25(6): 3441-53. N.A. Bracey, P.L. Beck, D.A. Muruve, S.A. Hirota, J. Guo, H.I. 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-1b. Exp Physiol 98(2): 462-472. J.A. MacDonald, L.D. Moffat, A. Al-Ghabkari, C. Sunderland, M.P. Walsh. (2013) Prostate apoptosis response-4 (Par-4) phosphorylation in vascular smooth muscle. Arch Biochem Biophys 535(1): 84-90. S.A. Hirota, V. Iablokov, S.E. Tulk, L.P. Schenck, H. Becker, J. Nguyen, S. Al Bashir, T. Dingle, A. Laing, J. Liu, Y. Li, J. Bolstad, G. Mulvey, G. 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(12): 4474-84 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. VanEeden, 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. 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. Thompson, K.A. Sharkey. (2012) Activation of neuronal P2X7 receptor pannexin-1 mediates death of enteric neurons during colitis. Nature Medicine 18(4): 600-604 M.E. Grassie, S. Sutherland, A. Ulke-Lemée, 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(43): 36356-69. L.D. Moffat, S. Brown, M.E. Grassie, A. Ulke-Lemee, L. 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. 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. (2011) The NLRP3 inflammasome plays key role in the regulation of intestinal homeostasis. Inflamm Bowel Dis. 17(6): 1359-1372