Newton, Robert - University of Calgary - Department of Cell Biology and Anatomy

个人简介

1984 - 1987 BSc: Biochemistry, Imperial College of Science and Technology, University of London. 1988 - 1992 PhD: Molecular Genetics, Royal Postgraduate Medical School, University of London. Supervisor: Dr. Gudrun E. Moore

研究领域

As a member of the Airways Inflammation Research Group (formerly the Respiratory Research Group), my core research interests are asthma, chronic obstructive pulmonary disease (COPD) and the drugs used to treat these conditions. In asthma, glucocorticoids (clinically referred to as corticosteroids) are inhaled to treat inflammation in the airways, whereas β2-adrenoceptor agonists are taken to combat the bronchoconstriction that occurs during asthma attacks . However, the mechanisms of anti-inflammatory glucocorticoid action are not fully understood and this means that it is difficult to rationally improve on these drugs. We are therefore working to improve the understanding of the anti-inflammatory actions of glucocorticoids. This represents my core research interest and has been central my work since the mid 1990s. However, in the control of asthma, and COPD, clinical evidence suggests that use of combination inhalers containing both a glucocorticoid and a long-acting β2-adrenoceptor agonist (LABA) improve the anti-inflammatory benefits of the glucocorticoid. This enhanced effect (clinical efficacy) is also poorly understood, but could be key to designing improved combination therapies. We, in collaboration with Prof. Mark Giembycz, are examining the molecular basis for the enhancement of glucocorticoid action by LABAs.

近期论文

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102 George T, Bell M, Chakraborty M, Siderovski DP, Giembycz MA, Newton R (In Press). Protective roles for Rgs2 in a mouse model of house dust mite-induced airways inflammation. PLOs One. 101 Altonsy MO, Mostafa MM, Gerber AN, Newton R (In Press). Long-acting β2-agonists promote glucocorticoid-mediated repression of NF-κB by enhancing expression of the feedback regulator, TNFAIP3. Am. J. Physiol. Lung Cell Mol Physiol. 100 Joshi T, Yan D, Hamed O, Tannheimer SL, Phillips GB, Wright CD, Kim M, Salmon M, Newton R, and Giembycz MA (2016). GS-5759, a Bi-functional β2 -Adrenoceptor agonist and phosphodiesterase 4 inhibitor for chronic obstructive pulmonary disease with a unique mode of action: Effects on gene expression in human airway epithelial cells. J. Pharmacol. Exp. Thera. E-pub. DOI: http://dx.doi.org/10.1124/jpet.116.237743 99 Shah S, King EM, Mostafa MM, Altonsy MO, and Newton R (2016). DUSP1 maintains IRF1 and leads to increased expression of IRF1-dependent genes: A mechanism promoting glucocorticoid-insensitivity. J. Biol. Chem. E-Pub. DOI: 10.1074/jbc.M116.728964. PMID: 27551049. 98 Leigh R, Mostafa MM, King MM, Rider CF, Shah S, Dumonceaux C, Traves SL, McWhae A, Kolisnik T, Kooi C, Slater DM, Kelly MM, Bieda M, Miller-Larsson A, and Newton R. (2016) An inhaled dose of budesonide induces genes involved in transcription and signaling in the human airways: enhancement of anti and pro-inflammatory effector genes. Pharma Res Per, 4(4), e00243, doi: 10.1002/prp2.243. 97 Shah S, Mostafa M, McWhae A, Traves SL, Newton R. (2016) Negative feed-forward control of tumor necrosis factor (TNF) by tristetraprolin (ZFP36) is limited by the mitogen-activated protein kinase phosphate, dual-specificity phosphatase 1 (DUSP1): Implications for regulation by glucocorticoids. J. Biol. Chem. 291, 110-125. PMID 26546680. 96 Rider CF, Shah S, Miller-Larsson A, Giembycz MA, Newton R. (2015) Cytokine-induced loss of glucocorticoid function: Effect of kinase inhibitors, long-acting β2-adrenoceptor agonist and glucocorticoid receptor ligands. PLOS One. 10(1):e0116773. PMID: 25625944 95 Joshi T, Johnson M, Newton R, Giembycz M. (2015) An analysis of glucocorticoid receptor-mediated gene expression in BEAS-2B human airway epithelial cells identifies distinct, ligand-directed, transcription profiles with implications for asthma therapeutics. Brit. J. Pharmacol. 172(5), 1360-78. PMID: 25393397 94 Joshi T, Johnson M, Newton R, Giembycz M. (2015) The long-acting β2-adrenoceptor agonist, indacaterol, enhances glucocorticoid receptor-mediated transcription in human airway epithelial cells in a gene- and agonist-dependent manner. Brit. J. Pharmacol. PMID: 25598440. E-pub. 93. BinMahfouz H, Yan D, Borthakur B, George T, Giembycz MA, Newton R. (2015) Superiority of combined phosphodiesterase PDE3/PDE4 inhibition over PDE4 inhibition alone on Glucocorticoid- and Long-acting β2-adrenoceptor agonist-induced gene expression in human airway epithelial cells. Mol. Pharmacol. 87, 64-76. PMID: 25324049 92. Shah S, King EM, Chandrasekhar A, Newton R. (2014) Roles of the mitogen-activated protein kinase (MAKP) phosphatase, DUSP1, in feedback control of inflammatory gene expression and repression by dexamethasone. J. Biol. Chem. E-pub., 289(19), 13367-79. 91. Holden NS, George T, Rider CF, Chandrasekhar A, Shah, S, Kaur M, Johnson M, Siderovski DP, Leigh R, Giembycz MA, Newton R. (2014) Induction of RGS2 expression by long-acting β2-adrenoceptor agonists and glucocorticoids in human airway epithelial cells. J. Pharmacol. Exp. Ther. 348, 12-24. PMID: 24163441 90. Greer S, Page CP, Joshi T, Yan D, Newton R, Giembycz MA. (2013) Concurrent activation of the adenosine A2B- and glucocorticoid receptors in human airway epithelial cells cooperatively induces genes with anti-inflammatory potential: a novel approach to treat COPD. J. Pharmacol. Exp. Ther. E-pub. 346, 473-485. PMID: 23820127 89. Rider CF, Miller-Larsson A, Proud D, Giembycz MA, Newton R. (2013) Modulation of transcriptional responses by poly(I:C) and human rhinovirus: Effect of long-acting β2-adrenoceptor agonists. Eur. J. Pharmacol., 708, 60-67. PMID: 23523474. 88. Moodley T, Wilson SM, Joshi T, Rider CF, Sharma P, Yan D, Newton R, Giembycz MA. (2013) Phosphodiesterase 4 inhibitors augment the ability of formoterol to enhance glucocorticoid-dependent gene transcription in human airway epithelial cells: a novel mechanism for the clinical efficacy of roflumilast in severe chronic obstructive pulmonary disease. Mol. Pharmacol. 83, 894-906. 87. King EM, Chivers JE, Rider CF, Minnich A, Giembycz MA, Newton R. (2013) Repression of inflammatory gene expression by glucocorticoids suggests roles for both transactivation and transrepression. PLOS One. 8(1),e53936. F1000 Prime recommended article 86. Tacon CE, Newton R, Proud D, Leigh R. (2012) Rhinovirus-induced MMP-9 expression is dependent on Fra-1, which is modulated by formoterol and dexamethasone. J. Immunol. 188, 4621-4630. 85. Manetsch M, Ramsay E, King E, Seidel P, Che W, Ge Q, Hibbs D, Newton R, Ammit A. (2012) Corticosteroids and β2-agonists upregulate mitogen-activated protein kinase phosphatase 1: In vitro mechanisms. Brit. J. Pharmacol. 166(7), 2049-2059. 84. Kelly MM, King EM, Rider CF, Gwozd C, Holden NS, Eddleston J, Zuraw B, Leigh R, O'Byrne PM, Newton R. (2012) Corticosteroid-induced gene expression in allergen-challenged asthmatic subjects taking inhaled budesonide. Brit. J. Pharmacol. 165, 1737-1747 83. Holden NS, Bell MJ, Rider CF, King EM, Gaunt DD, Leigh R, Johnson M, Siderovski DP, Heximer SP, Giembycz MA, Newton R. (2011) β2-Adrenoceptor agonist-induced RGS2 expression is a genomic mechanism of bronchoprotection that is enhanced by glucocorticoids. Proc. Natl. Acad. Sci. USA. 108, 19713-19718.