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Professor Tim Palmer

PositionProfessor of Pharmacology, Head of Pharmacology and Experimental Therapeutics
Location2.16b Norcroft
DepartmentSchool of Pharmacy
Telephone01274 234662
EmailT.Palmer1@bradford.ac.uk
Twitter@proftimpalmer
LinkedInVisit my LinkedIn profile
ORCID0000-0002-9803-7164

Research Interests (key words only)

Cardiovascular Disease; Regulation of Cytokine Signalling; Identification and Validation of New Signalling Pathway Targets

PhD Supervision

15 students successfully supervised to completion.

  • Current students are: Gillian Durham (BHF) - Prostanoid-mediated inhibition of IL-6 trans-signalling in pulmonary arterial hypertension; a role for Epac1-mediated induction of "suppressor of cytokine signalling 3" (SOCS3)
  • Nasser Alotaiq (Saudi Governmentt Scholarship) – Cavin-1-mediated regulation of suppressor of cytokine signalling 3 (SOCS3) function

Teaching and Supervisory Responsibilities

MPharm

Unit lead:

  • Foundation Skills 1, Unit 1 - Molecules of Life
  • Transport 1, Unit 5 - Cardiovascular System 2

Unit team member:

  • Transport 2, Unit 3 - Cardiovascular System 1

Student Selected Component:

  • S-strand (Systematic Review) Lead

Personal Academic Tutor

Administrative Responsibilities

  • Head of Pharmacology and Experimental Therapeutics
  • Independent Scientific Advisory Consultant (ISAC) for Ethical Tissue
  • Member of Biomedical, Natural, Physical and Health Sciences Research Ethics Panel (BNPHS REP)
  • Member of Faculty of Life Sciences Research and Knowledge Transfer Committee

Study History

  • BSc (Hons) First Class in Biochemistry, 1987, University of Manchester
  • PhD in Biochemistry, 1991, University of Glasgow

Professional History

  • 1997-2014: Lecturer (1997-2004), Senior Lecturer (2004-2008) and Reader (2008-2014), University of Glasgow, Scotland, UK
  • 1991-1997: Postdoctoral Research Associate and American Heart Association Research Fellow, Duke University Medical Centre, Durham, North Carolina, USA
  • 2015 – present: Honorary Senior Research Fellow, Institute of Cardiovascular & Medical Sciences, University of Glasgow, Scotland, UK

Professional Activities

  • Local Ambassador, Biochemical Society
  • Member of the British Society for Cardiovascular Research
  • Member of the British Society of Cell Biology
  • Member of the Society for Endocrinology
  • Member of the American Association for the Advancement of Science
  • Member of the British Pharmacological Society

Research Areas

The JAK-STAT Pathway and Cardiovascular Disease

Despite improvements in preventative treatments, cardiovascular diseases (CVDs) such as congestive heart disease and stroke still claim over 130,000 lives each year in the UK. Localised inflammation of branch points within large blood vessels is a pivotal event in atherosclerotic plaque formation. Inflammation is driven by long-term exposure to chemical signals termed "cytokines" which trigger multiple intracellular pathways that ultimately lead to the defective vascular cell function responsible for cardiovascular disease.

My laboratory focuses on cytokines that activate a particularly important signalling pathway in vascular endothelial and smooth muscle cells termed the "JAK-STAT" pathway. We are particularly interested in processes that turn this pathway off, since its chronic activation is a key determinant of disease. However, relatively little is known about the inhibitory mechanisms responsible for turning off JAK-STAT activation in vascular cells and nothing is known regarding their status in blood vessels from patients with CVD. By expanding our knowledge of the molecular processes involved, we aim to identify new targets for optimal drug treatment of affected individuals.

Inhibition of JAK-STAT signalling by AMPK

AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase involved in the regulation of cellular and organismal metabolism and has been proposed to be a candidate target for therapeutic intervention in the treatment of type 2 diabetes and insulin resistance. We have identified a novel molecular mechanism linking AMPK to the rapid suppression of pro-inflammatory JAK-STAT-mediated signalling responses. Crucially, the ability of this pathway to inhibit JAK-STAT signalling is compromised in cells from patients with coronary artery disease. We are currently examining the molecular basis of this defect in order to devise strategies to rescue function in disease.

JAK-STAT signalling and the development of pulmonary hypertension (PAH)

IL-6 is a key driver of the chronic inflammation observed in the pulmonary vasculature during the development of PAH, a debilitating condition with a poor prognosis. Individuals who are homozygous for inactivating mutations within the BMPRII receptor gene are at increased risk of developing this condition. We are investigating how inactivation of BMPRII signalling is mechanistically linked to the establishment of the chronic inflammation that drives the observed pulmonary vessel remodelling responsible for PAH.

Manipulation of SOCS3 stability and function in CVD

It is becoming clear that as well as interacting with cytokine receptors, SOCS-3 has multiple intracellular roles. An important aspect of its function is as the specificity determinant of a complex that controls the ubiquitylation of intracellular proteins, thus targeting them for proteasomal degradation. We have used quantitative proteomics to identify several new SOCS3-regulated proteins and the biological importance of their interaction with SOCS3 is currently being investigated. We are also examining how inhibiting the ubiquitylation of SOCS3 itself could be used to increase its stability and thus reduce the localized inflammation and smooth cell migration and proliferation responsible for the re-stenosis that limits long-term success of angioplasty and coronary artery bypass graft procedures.

Current Projects

  • Targeting epigenome and microbiome for management of skin regeneration and treatment of skin diseases (MRC Confidence in Concept: 2017-2019)
  • Therapeutic targeting of JAK-STAT signalling pathways responsible for vascular re-stenosis in Type 2 diabetes (PhD studentship scholarship: 2017-2020)
  • Real-time imaging of molecular mechanisms underlying synaptic dysfunction and neurodegeneration in Alzheimer's disease (Alzheimer’s Research UK equipment grant 2016)
  • Prostanoid-mediated inhibition of IL-6 trans-signalling in pulmonary arterial hypertension; a role for Epac1-mediated induction of "suppressor of cytokine signalling 3" (SOCS3) (BHF non-clinical PhD studentship: 2016-2019)
  • Regulation of anti-inflammatory gene expression in vascular endothelial cells by EPAC1 (BHF project grant: 2015-2018)
  • Suppression of IL-6 signalling by BMP4: a "missing link" in the development of pulmonary arterial hypertension? (BHF project grant: 2014-2018)
  • Inhibition of endothelial mitogen-activated protein kinases by AMP-activated protein kinase (BHF project grant: 2014-2017)
  • Cavin-1-mediated regulation of suppressor of cytokine signalling 3 (SOCS3) function (Saudi Government PhD studentship: 2012-2017)

Research Collaborations

  • Dr Talat Nasim (University of Bradford)
  • Dr Wayne Roberts (University of Bradford)
  • Dr Kirsten Riches (University of Bradford)
  • Professor Vladimir Botchkarev (University of Bradford)
  • Dr Ian Salt (University of Glasgow)
  • Professor Mandy MacLean (University of Glasgow)
  • Professor Andrew Baker (University of Edinburgh)
  • Professor George Baillie (University of Glasgow)
  • Professor Christian Delles (University of Glasgow)
  • Dr Stephen Yarwood (Heriot-Watt University)
  • Professor Simon Jones (University of Cardiff)
  • Dr Luke Chamberlain (University of Strathclyde)
  • Professor Paul Pilch (Boston University Medical School, USA)
  • Professor Fred Schaper (University of Magdeburg, Germany)

Publications

"Mancini SJ, White AD, Bijland S, Rutherford C, Graham D, Richter EA, Viollet B, Touyz RM, Palmer TM, Salt IP. Activation of AMP-activated protein kinase rapidly suppresses multiple pro-inflammatory pathways in adipocytes. Mol Cell Endocrinol, 2017;440:44-456.

Rutherford C, Speirs C, Williams JJL, Ewart M-A, Mancini SJ, Hawley SA, Delles C, Viollet B, Costa-Pereira AP, Baillie GS, Salt IP, Palmer TM. Phosphorylation of Janus kinase 1 (JAK1) by AMP-activated protein kinase (AMPK) links energy sensing to anti-inflammatory signaling. Sci Signal. 2016;9:ra109.

Heathcote HR, Mancini SJ, Strembitska A, Jamala K, Reihill JA, Palmer TM, Gould GW, Salt IP. Protein kinase C phosphorylates AMP-activated protein kinase α1 Ser487. Biochem J, 2016;473:4681-4697."

Rutherford C, Palmer TM. Regulation of Adenosine Receptor Desensitisation and Function, for "Adenosine Signaling Mechanisms: Pharmacology, Functions and Therapeutic Aspects" 2015 (Editors. V Ramkumar, RP de Carvalho) Nova Science Publishing ISBN: 978-1-63483-186-4

Parnell E, Palmer TM, Yarwood SJ. The future of EPAC-targeted therapies: agonism versus antagonism. Trends Pharmacol Sci. 2015;36:203-214

Williams JJL, Munro KMA, Palmer TM. Role of ubiquitylation in controlling suppressor of cytokine signalling 3 (SOCS3) function and expression. Cells 2014; 3:546-562; doi:10.3390/cells3020546

Williams JJL, Palmer TM. Cavin-1: caveolae-dependent signalling and cardiovascular disease. Biochem. Soc. Trans. 2014; 42:284-88

Rutherford C, Childs S, Ohotski J, McGlynn L, Riddick M, MacFarlane S, Tasker D, Pyne S, Pyne NJ, Edwards J, Palmer TM. Regulation of cell survival by sphingosine-1-phosphate receptor S1P1 via reciprocal ERK-dependent suppression of Bim and PI-3-kinase/protein kinase C-mediated up-regulation of Mcl-1, Cell Death and Disease 2013;4, e927; doi:10.1038/cddis.2013.455

Cannavo A, Rengo G, Liccardo D, Pagano G, Zincarelli C, De Angelis MC, Puglia R, Di Pietro E, Rabinowitz J, Barone MV, Cirillo P, Trimarco B, Palmer TM, Koch W, Leosco D, Rapacciuolo A. ß1-adrenergic receptor and Sphingosine-1-phosphate receptor 1 reciprocal down-regulation influences cardiac hypertrophic response and progression toward heart failure: protective role of S1PR1 cardiac gene therapy. Circulation. 2013 Oct 8;128(15):1612-1622

Long JS, Crighton D, O'Prey J, Mackay G, Zheng L, Palmer TM, Gottlieb E, Ryan KM. Extracellular adenosine sensing-a metabolic cell death priming mechanism downstream of p53. Mol Cell. 2013 May 9;50(3):394-406

Dondelinger F, Rogers S, Filippone M, Cretella R, Palmer TM, Smith R, Millar A, Husmeier D. (2012) Parameter inference in mechanistic models of cellular regulation and signalling pathways using gradient matching. In: WCSB2012 - 9th International Workshop on Computational Systems Biology, 4-6 Jun 2012, Ulm, Germany

Salt IP, Palmer TM. Exploiting the anti-inflammatory effects of AMP-activated protein kinase activation. Expert Opin. Investig. Drugs, 2012; 21:1155-67

Jones SE, Palmer TM. Protein kinase A-mediated phosphorylation of RhoA on serine 188 triggers the rapid induction of a neuroendocrine-like phenotype in prostate cancer epithelial cells. Cell. Signal. 2012; 24:1504–14

Rutherford C, Woolson HD, Palmer TM. Cross-Regulation of JAK-STAT Signalling: Implications For Approaches to Combat Chronic Inflammatory Diseases and Cancers in "Protein Kinases / Book 2 (Editor: Dr. Gabriela Da Silva Xavier)" In-Tech Publishers, 2012, ISBN 979-953-307-890-7

Williams JJL, Palmer TM. Unbiased identification of substrates for the Epac1-inducible E3 ubiquitin ligase component SOCS-3. Biochem. Soc. Trans. 2012; 40:215-18

Milne GR, Palmer TM, Yarwood SJ. Novel control of cAMP-regulated transcription in vascular endothelial cells. Biochem Soc Trans. 2012; 40:1-5

Sands WA, Woolson HD, Yarwood SJ, Palmer TM. Exchange protein directly activated by cyclic AMP-1-regulated recruitment of CCAAT/enhancer-binding proteins to the suppressor of cytokine signaling-3 promoter. Methods Mol Biol. 2012; 809:201-14

Parnell E, Smith BO, Palmer TM, Terrin A, Zaccolo M, Yarwood SJ. Regulation of the Inflammatory Response of Vascular Endothelial Cells by EPAC1. Br J Pharmacol. 2012; 166:434–446

Williams JJL, Palmer TM. Interleukin-6 (IL6) signalling and its role in the development of cardiovascular disease, in "Endothelium and Epithelium: Composition, Functions and Pathology" (Editors: João Carrasco and Matheus Mota), 157-173, Nova Publishers, 2011, ISBN 978-1-61470-874-2

Milne GR, Palmer, TM. Anti-inflammatory and immunosuppressive effects of the A2A adenosine receptor. The Scientific World Journal 2011 11:320-339

Rutherford C, Palmer TM. Molecular basis of protective anti-inflammatory signalling by cyclic AMP in the vascular endothelium, in "Systems Biology of Signaling Networks" (Editor Sangdun Choi). 561-588, Springer, 2010, ISBN: 978-1-4419-5796-2

Safhi MMA, Rutherford C, Ledent C, Sands WA, Palmer TM. Priming of signal transducer and activator of transcription proteins for cytokine-triggered polyubiquitylation and degradation by the A2A adenosine receptor. Mol. Pharmacol. 2010 77:968–978

Mundell SJ, Matharu A-L, Palmer TM, Benovic JL, Kelly E. Deletion of the distal COOH-terminus of the A2B adenosine receptor switches agonist-induced internalisation to an arrestin- and clathrin-independent pathway and inhibits receptor recycling. Br J Pharmacol 2010 159:518–533

Woolson HD, Thompson VS, Rutherford C, Yarwood SJ, Palmer TM. Selective inhibition of cytokine-activated extracellular signal-regulated kinase by cyclic AMP via Epac1-dependent induction of suppressor of cytokine signalling-3. Cell. Signal. 2009 21:1706–1715

Borland G, Bird R, Palmer TM, Yarwood SJ. Activation of protein kinase Cα by EPAC1 is required for the ERK- and C/EBPß-dependent induction of the SOCS-3 gene by cyclic AMP in COS1 cells. J. Biol. Chem. 2009 284:17391–17403

Yarwood SJ, Borland G, Sands WA, Palmer TM. Identification of C/EBPs as EPAC-activated transcription factors that mediate the induction of the SOCS-3 gene. J Biol Chem. 2008 283(11):6843-53

Mair KM, MacLean MR, Morecroft I, Dempsie Y, Palmer TM. Novel interactions between the 5-HT transporter, 5-HT1B receptors and Rho kinase in vivo and in pulmonary fibroblasts. Br J Pharmacol. 2008 155:606-616

Palmer TM, Trevethick MA. Suppression of inflammatory and immune responses by the A(2A) adenosine receptor: an introduction. Br J Pharmacol. 2008 153:S27–S34

Sands WA, Palmer TM. Regulating gene transcription in response to cyclic AMP elevation. Cell Signal. 2008 Mar;20(3):460-6

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