Professor, Department of Physiology and Pharmacology
University of Calgary, Calgary, AB
Since the late 1960s, Dr. Hollenberg has made sustained and conceptually paradigm-shifting contributions in the area of molecular pharmacology of hormone action, as related to signalling by hormone-like mediators, including insulin, epidermal growth factor (EGF) and proteolytic enzymes. He is also a professional artist, whose focus is on Chinese brushwork. His work can be found in international collections. His scientific contributions have been recognized by membership in the Royal Society of Canada and a number of research-related awards: (1) the Pharmacological Society of Canada’s 1999 Novartis award for outstanding contributions to pharmacology in Canada, (2) The Canadian Society of Clinical Investigation 2009 Distinguished Scientist award, (3) the Royal Society of Canada’s 2011 McLaughlin medal for sustained research excellence and just recently, (4) the CSCI/Royal College Henry Friesen Award for 2012 for demonstrated leadership in developing biomedical research at local, national and international levels and (5) the 2013 . The E. K. Frey – E. Werle Commemorative Gold Medal, for outstanding contributions on the role of the kallikrein-kinin system and related subjects in health and disease and with significant influence on the development in these fields.
Born into a Winnipeg family seen by some as a “Canadian Medical Dynasty” (physician parents; 4 uncles one aunt and many cousins also all MDs), Morley first pursued his training in Chemistry and Pharmacology, rather than in medicine. With degrees in chemistry (B.Sc. Honours; MSc.) from the University of Manitoba, he went on as a Rhodes Scholar to obtain his D. Phil. in pharmacology at Oxford University in England. At that point, his longstanding interest in medicine took over, and he attended the Johns Hopkins University School of Medicine where he received his MD degree and clinical training as a medical Intern at the Johns Hopkins Hospital. Stepping out of his internship to obtain post-doctoral training, he was soon appointed as a member of the Hopkins Departments of Pharmacology & Therapeutics and Medicine, as a Howard Hughes Investigator. Moving to The University of Calgary in 1979, he headed The Department of Pharmacology & Therapeutics for a decade, and continues to serve jointly as a member of both the newly named Department of Physiology & Pharmacology and the Department of Medicine. His Calgary laboratory has thrived over the years with a recent focus on the hormone-like roles of proteinases that regulate the innate immune response by activating proteinase-activated receptors (PARs). To this day, he participates vigorously in the research and teaching activities of the University of CalgaryMedical Faculty, with an added role as a Co-Director, with Dr. Paul Beck, of the Faculty’s Leaders in Medicine Programme, which trains the MD-PhD/MD-MSc individuals who will create the Medicine of the Future. His supportive immediate family, comprising his long-time partner, Joan and their two children (Elisa & Daniel), has grown to include Elisa’s partner, Tarver, and Daniel’s wife, Seema with their two children, Mira and Isaac. Thus, issues of Science, Art and Family frame the essence of Morley’s future.
Ramachandran R, Hyun E, Zhao L, Lapointe TK, Chapman K, Hirota CL, Ghosh S, McKemy DD, Vergnolle N, Beck PL, Altier C, Hollenberg MD. TRPM8 activation attenuates inflammatory responses in mouse models of colitis. Proc Natl Acad Sci U S A. 110:7476-7481, 2013.
Fernández-Blanco JA, Hollenberg MD, Martínez V, Vergara P. PAR-2-mediated control of barrier function and motility differs between early and late phases of postinfectious gut dysfunction in the rat. Am J Physiol Gastrointest Liver Physiol. 304(4):G390-400, 2013.
Hollenberg MD. Mentors And The Butterfly Effect: Triggers For Discovering Signalling by Proteinases via Proteinase-Activated Receptors (PARs) And More. Clin Invest Med. 2012 Feb 1;35(6):E378.
Nichols HL, Saffeddine M, Theriot BS, Hegde A, Polley D, El-Mays T, Vliagoftis H, Hollenberg MD, Wilson EH, Walker JK, DeFea KA. β-Arrestin-2 mediates the proinflammatory effects of proteinase-activated receptor-2 in the airway. Proc Natl Acad Sci U S A. 109:16660-16665, 2012.
Russell FA, Schuelert N, Veldhoen VE, Hollenberg MD, McDougall JJ. Proteinase-activated receptor-2 (PAR(2) ) activation sensitises primary afferents and causes leukocyte rolling and adherence in the rat knee joint. Br J Pharmacol. 167:1665-78, 2012
Hirota CL, Moreau F, Iablokov V, Dicay M, Renaux B, Hollenberg MD, Macnaughton WK. Epidermal growth factor receptor transactivation is required for proteinase-activated receptor-2-induced COX-2 expression in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2012 Jul;303(1):G111-9
Ramachandran R, Eissa A, Mihara K, Oikonomopoulou K, Saifeddine M, Renaux B, Diamandis E, Hollenberg MD. Proteinase-activated receptors (PARs): differential signalling by kallikrein-related peptidases KLK8 and KLK14. Biol Chem. 2012 Apr 1;393(5):421-7
Chung H, Hamza M, Oikonomopoulou K, Gratio V, Saifeddine M, Virca GD, Diamandis EP, Hollenberg MD, Darmoul D. Kallikrein-related peptidase signaling in colon carcinoma cells: targeting proteinase-activated receptors. Biol Chem. 2012 Apr 1;393(5):413-20.
Kaufmann R, Hollenberg MD. Proteinase-Activated Receptors (PARs) and Calcium Signaling in Cancer. Adv Exp Med Biol. 740:979-1000, 2012.
Ramachandran R, Noorbakhsh F, Defea K, Hollenberg MD. Targeting proteinase-activated receptors: therapeutic potential and challenges. Nat Rev Drug Discov. 3;11(1):69-86. 2012
Hollenberg MD. Novel insights into the delayed vasospasm following subarachnoid haemorrhage: Importance of proteinase signalling. Br J Pharmacol. 165(1):103-105. 2012
Takei-Taniguchi R, Imai Y, Ishikawa C, Sakaguchi Y, Nakagawa N, Tsuda T, Hollenberg MD, Yamanishi K., Interleukin-17- and protease-activated receptor 2-mediated production of CXCL1 and CXCL8 modulated by cyclosporine A, vitamin D(3) and glucocorticoids in human keratinocytes., J Dermatol. doi: 10.1111/j.1346-8138.2011.01462.x. 2011]
Chung H, Hamza M, Oikonomopoulou K, Gratio V, Saifeddine M, Virca GD, Diamandis EP, Hollenberg MD, Darmoul D., Kallikrein-related peptidase signaling in colon carcinoma cells: Targeting proteinase-activated receptors (PARs).,Biol Chem. 2011 .
Sharma N, Kumar R, Renaux B, Saifeddine M, Nishikawa S, Mihara K, Ramachandran R, Hollenberg MD, Rancourt DE., Implantation serine proteinase 1 exhibits mixed substrate specificity that silences signaling via proteinase-activated receptors., PLoS One.;6(11):e27888, .2011
Acharjee S, Zhu Y, Maingat F, Pardo C, Ballanyi K, Hollenberg MD, Power C., Proteinase-activated receptor-1 mediates dorsal root ganglion neuronal degeneration in HIV/AIDS., Brain. 134(Pt 11):3209-2321, 2011
Gratio V, Loriot C, Virca GD, Oikonomopoulou K, Walker F, Diamandis EP, Hollenberg MD, Darmoul D., Kallikrein-related peptidase 14 acts on proteinase-activated receptor 2 to induce signaling pathway in colon cancer cells. Am J Pathol., 179(5):2625-2636.2011
Hyun E, Ramachandran R, Hollenberg MD, Vergnolle N. Mechanisms behind the anti-inflammatory actions of insulin. Crit Rev Immunol.;31(4):307-340. 2011
El Mays TY, Saifeddine M, Choudhury P, Hollenberg MD, Green FH. Carbon dioxide enhances substance P-induced epithelium-dependent bronchial smooth muscle relaxation in Sprague-Dawley rats.Can J Physiol Pharmacol. 89(7):513-520. 2011
Carson L, Cathcart GR, Scott CJ, Hollenberg MD, Walker B, Ceri H, Gilmore BF. Comprehensive inhibitor profiling of the Proteus mirabilis metalloprotease virulence factor ZapA (mirabilysin). Biochimie. 293(10):1824-1827, 2011.
Li Y, Mihara K, Saifeddine M, Krawetz A, Lau DC, Li H, Ding H, Triggle CR, Hollenberg MD. Perivascular adipose tissue-derived relaxing factors: release by peptide agonists via proteinase-activated receptor-2 (PAR(2) ) and non-PAR(2) mechanisms. Br J Pharmacol. 164(8):1990-2002. 2011
Ramachandran R, Mihara K, Chung H, Renaux B, Lau CS, Defea KA, Bouvier M, Hollenberg MD. Neutrophil elastase acts as a biased agonist for proteinase activated receptor-2 (PAR2). J Biol Chem. 286(28):24638-24648, 2011.
Shpacovitch VM, Feld M, Holzinger D, Kido M, Hollenberg MD, Levi-Schaffer F, Vergnolle N, Ludwig S, Roth J, Luger T, Steinhoff M. Role of proteinase-activated receptor-2 in anti-bacterial and immunomodulatory effects of interferon-γ on human neutrophils and monocytes. Immunology. 133(3):329-339, 2011.
Arizmendi NG, Abel M, Mihara K, Davidson C, Polley D, Nadeem A, El Mays T, Gilmore BF, Walker B, Gordon JR, Hollenberg MD, Vliagoftis H. Mucosal allergic sensitization to cockroach allergens is dependent on proteinase activity and proteinase- activated receptor-2 activation. J Immunol. 186(5):3164-3172, 2011
Adams MN, Ramachandran R, Yau MK, Suen JY, Fairlie DP, Hollenberg MD, Hooper JD. Structure, function and pathophysiology of protease activated receptors. Pharmacol Ther. 130(3):248-282, 2011.
Goldblum SE, Rai U, Tripathi A, Thakar M, De Leo L, Di Toro N, Not T, Ramachandran R, Puche AC, Hollenberg MD, Fasano A. The active Zot domain (aa 288-293) increases ZO-1 and myosin 1C serine/threonine phosphorylation, alters interaction between ZO-1 and its binding partners, and induces tight junction disassembly through proteinase activated receptor 2 activation. FASEB J. 25(1):144-158, 2011
Kim M, Hansen KK, Davis L, van Marle G, Gill MJ, Fox JD, Hollenberg MD, Rancourt DE, Lee PW, Yun CO, Johnston RN. Z-FA-FMK as a novel potent inhibitor of reovirus pathogenesis and oncolysis in vivo. Antivir Ther.15(6):897-905, 2010
Wang J, Boerma M, Kulkarni A, Hollenberg MD, Hauer-Jensen M. Activation of protease activated receptor 2 by exogenous agonist exacerbates early radiation injury in rat intestine. Int J Radiat Oncol Biol Phys.77(4):1206-1212. 2010
Noorbakhsh F, Ramachandran R, Barsby N, Ellestad KK, LeBlanc A, Dickie P, Baker G, Hollenberg MD, Cohen EA, Power C. MicroRNA profiling reveals new aspects of HIV neurodegeneration: caspase-6 regulates astrocyte survival. FASEB J.24(6):1799-812, 2010
Blanco I, Béritze N, Argüelles M, Cárcaba V, Fernández F, Janciauskiene S, Oikonomopoulou K, de Serres FJ, Fernández-Bustillo E, Hollenberg MD. Abnormal overexpression of mastocytes in skin biopsies of fibromyalgia patients.Clin Rheumatol. 2010 Apr 30. [Epub ahead of print]
Csorba TR, Lyon AW, Hollenberg MD. Autoimmunity and the pathogenesis of type 1 diabetes. Crit Rev Clin Lab Sci. 47(2):51-71, 2010
Oikonomopoulou K, Diamandis EP, Hollenberg MD. Kallikrein-related peptidases: proteolysis and signaling in cancer, the new frontier. Biol Chem.391(4):299-310, 2010
Oikonomopoulou K, Batruch I, Smith CR, Soosaipillai A, Diamandis EP, Hollenberg MD. Functional proteomics of kallikrein-related peptidases in ovarian cancer ascites fluid. Biol Chem. 391(4):381-90, 2010
Hollenberg MD.Getting the message across: pathophysiology and signaling via receptors for polypeptide hormones and proteinases. Clin Invest Med.1; 33(2):E133, 2010
Georgy SR, Pagel CN, Wong DM, Sivagurunathan S, Loh LH, Myers DE, Hollenberg MD, Pike RN, Mackie EJ. Proteinase-activated receptor-2 (PAR2) and mouse osteoblasts: Regulation of cell function and lack of specificity of PAR2-activating peptides. Clin Exp Pharmacol Physiol. 37(3):328-36, 2010
Hyun E, Ramachandran R, Cenac N, Houle S, Rousset P, Saxena A, Liblau RS, Hollenberg MD, Vergnolle N. Insulin modulates protease-activated receptor 2 signaling: implications for the innate immune response. J Immunol. 1; 184(5):2702-9, 2010
Al-Ani B, Hewett PW, Cudmore MJ, Fujisawa T, Saifeddine M, Williams H, Ramma W, Sissaoui S, Jayaraman PS, Ohba M, Ahmad S, Hollenberg MD, Ahmed A. Activation of proteinase-activated receptor 2 stimulates soluble vascular endothelial growth factor receptor 1 release via epidermal growth factor receptor transactivation in endothelial cells. Hypertension. 55(3):689-97, 2010
Kaufmann R, Oettel C, Horn A, Halbhuber KJ, Eitner A, Krieg R, Katenkamp K, Henklein P, Westermann M, Böhmer FD, Ramachandran R, Saifeddine M, Hollenberg MD, Settmacher U. Met receptor tyrosine kinase transactivation is involved in proteinase-activated receptor-2-mediated hepatocellular carcinoma cell invasion. Carcinogenesis. 30(9):1487-96, 2009
Androutsou ME, Saifeddine M, Hollenberg MD, Matsoukas J, Agelis G. Design, synthesis and biological evaluation of non-peptide PAR1 thrombin receptor antagonists based on small bifunctional templates: arginine and phenylalanine side chain groups are keys for receptor activity. Amino Acids.; 38(4):985-90, 2009
Ramachandran R, Mihara K, Mathur M, Rochdi MD, Bouvier M, Defea K, Hollenberg MD. Agonist-biased signaling via proteinase activated receptor-2: differential activation of calcium and mitogen-activated protein kinase pathways. Mol Pharmacol. 76(4):791-801, 2009
Swystun VA, Renaux B, Moreau F, Wen S, Peplowski MA, Hollenberg MD, MacNaughton WK. Serine proteases decrease intestinal epithelial ion permeability by activation of protein kinase Czeta. Am J Physiol Gastrointest Liver Physiol. 297(1):G60-70, 2009
Pittman QJ, Hollenberg MD. Urotensin I-CRF-Urocortins: a mermaid’s tail. Gen Comp Endocrinol.164(1):7-14, 2009
Zhu Y, Vergote D, Pardo C, Noorbakhsh F, McArthur JC, Hollenberg MD, Overall CM, Power C. CXCR3 activation by lentivirus infection suppresses neuronal autophagy: neuroprotective effects of antiretroviral therapy. FASEB J.(9):2928-41, 2009
Xue M, Hollenberg MD, Demchuk A, Yong VW. Relative importance of proteinase-activated receptor-1 versus matrix metalloproteinases in intracerebral hemorrhage-mediated neurotoxicity in mice. Stroke. 40(6):2199-204, 2009
Wilson BJ, Harada R, Leduy L, Hollenberg MD, Nepveu A.The CUX1 transcription factor is a downstream effector of the proteinase activated receptor 2 (PAR2). J Biol Chem. 284(1):36-45, 2009.
Ellis A, Cheng ZJ, Li Y, Jiang YF, Yang J, Pannirselvam M, Ding H, Hollenberg MD, Triggle CR.Effects of a Western diet versus high glucose on endothelium-dependent relaxation in murine micro- and macro-vasculature. Eur J Pharmacol. 601(1-3):111-117, 2008
Hansen KK, Oikonomopoulou K, Baruch A, Ramachandran R, Beck P, Diamandis EP, Hollenberg MD. Proteinases as hormones: targets and mechanisms for proteolytic signaling. Biol Chem. 389(8):971-982, 2008
Sharma N, Oikonomopoulou K, Ito K, Renaux B, Diamandis EP, Hollenberg MD, Rancourt DE. Substrate specificity determination of mouse implantation serine proteinase and human kallikrein-related peptidase 6 by phage display. Biol Chem. 389(8):1097-1105, 2008
Rallabhandi P, Nhu QM, Toshchakov VY, Piao W, Medvedev AE, Hollenberg MD, Fasano A, Vogel SN. Analysis of PAR2 and TLR4 signal transduction: A novel paradigm for receptor cooperativity. J Biol Chem.5; 283(36):24314-24325, 2008.
Oikonomopoulou K, Hansen KK, Baruch A, Hollenberg MD, Diamandis EP. Immunofluorometric activity-based probe analysis of active KLK6 in biological fluids. Biol Chem. 389(6):747-756, 2008
Hollenberg MD, Oikonomopoulou K, Hansen KK, Saifeddine M, Ramachandran R, Diamandis EP. Kallikreins and proteinase-mediated signaling: proteinase-activated receptors (PARs) and the pathophysiology of inflammatory diseases and cancer. Biol Chem. 389(6):643-651, 2008.
Hollenberg MD, Renaux B, Hyun E, Houle S, Vergnolle N, Saifeddine M, Ramachandran R. Derivatized 2-furoyl-LIGRLO-amide, a versatile and selective probe for proteinase-activated receptor 2: binding and visualization. J Pharmacol Exp Ther. 326 (2):453-462, 2008.
Shpacovitch V, Feld M, Hollenberg MD, Luger TA, Steinhoff M.Role of protease-activated receptors in inflammatory responses, innate and adaptive immunity. J Leukoc Biol(6):1309-1322, 2008.
Hansen KK, Oikonomopoulou K, Li Y, Hollenberg MD. Proteinases, proteinase-activated receptors (PARs) and the pathophysiology of cancer and diseases of the cardiovascular, musculoskeletal, nervous and gastrointestinal systems.Naunyn Schmiedebergs Arch Pharmacol.377(4-6):377-392, 2008.
Feld M, Shpacovitch VM, Ehrhardt C, Kerkhoff C, Hollenberg MD, Vergnolle N, Ludwig S, Steinhoff M.Agonists of proteinase-activated receptor-2 enhance IFN-gamma-inducible effects on human monocytes: role in influenza A infection. J Immunol 180(10):6903-6910, 2008.
Van der Merwe JQ, Hollenberg MD, Macnaughton WK. EGF Receptor Transactivation, and MAP Kinase Mediate Proteinase-Activated Receptor-2-Induced Chloride Secretion in Intestinal Epithelial Cells Am J Physiol Gastrointest Liver Physiol. 294(2):G441-451, 2008.
Ramachandran R, Hollenberg MD. Proteinases and signalling: pathophysiological and therapeutic implications via PARs and more. Br J Pharmacol. 153 Suppl 1:S263-282, 2008.
Wang H, Wen S, Bunnett NW, Leduc R, Hollenberg MD, Macnaughton WK. Proteinase-activated Receptor-2 Induces Cyclooxygenase-2 Expression through -Catenin and Cyclic AMP-response Element-binding Protein. J Biol Chem. 283(2):809-815, 2008.
K. Oikonomopoulou, K. Hansen, K. Chapman, N. Vergnolle, E.P. Siamandis, M.D. Holllenberg. Kallikrein-mediated activation of PARs in inflammation and nociception.Inflamm. Res. 56, Suuplement 3 S1-S4, 2008.
Hollenberg MD. Professor Karl Lederis (1920-2007): always fishing for new ideas Gen Comp Endocrinol. 164(1):4-5, 2009
Yamada S, Elhlert FJ, Hollenberg MD. 5th International Symposium on receptor mechanisms, signal transduction and drug effects. Naunyn Schmiedebergs Arch Pharmacol. 377(4-6):267-268, 2008