Role
Dr Mark Paul-Clark (Senior Lecturer in Pharmacology) is an inflammation scientist in the Pharmacology Team providing postgraduate and undergraduate provision. Course lead for MSc Pharmacology (2022-2024). His research area focuses on the impact of inflammation leading to maladaptation of the immune system, vasculature and neurons causing pathophysiological consequences.
Career overview
Dr Paul-Clark completed his PhD (2003) in the impact of nitric oxide in acute and chronic inflammation at the William Harvey Research Institute (WHRI) at Queen Mary University London. His first post-doctoral position was part funded by NiCOX and WHRI and focused on designing a novel nitric oxide releasing glucocorticoid for the treatment of arthritis. This was followed by a second post-doc at the National Heart and Lung Institute (Imperial College) investigating signal transduction and functional consequences of Toll-like receptors (TLRs) activation in chronic obstructive pulmonary disease and sepsis. This work led to two fellowships from the British Lung Foundation and Wellcome Trust investigating TLR2 as a novel receptor for oxidants in immune cells and the vasculature. This led to a focus on the impact of oxidative stress in the control of intracellular iron metabolism on immune cell function.
Research areas
De Paul-Clark major areas of research are:
In the immune system monocytes and macrophages provide a pivotal check point for both acute and chronic inflammation. These cells are the dynamic link between innate and adaptive immunity with the power to activate during inflammatory episodes or supress when present in tumours immune function. These cells are not only essential for the removal of the inflammogen, but also influence in tissue remodelling. When this is done well, it is a salutary process, but often tissue resident macrophages are dysfunctional and cause pathophysiological changes in host tissue. One such examples of this is in peripheral neuropathies caused by chemotherapy and diabetes leading to long-term pain. Understanding the relationship between resident macrophages and peripheral tissue will help inform the design of better therapeutics for the future. This can be done more effectively by first creating a model within python and scenario testing informing better experimental design.
Cardiovascular disease is the major cause of mortality and morbidity. This is because cardiovascular deterioration and failure leads to poor life course prognosis and is linked to the fact that all cells in the body are connected to a vascular supply which maintains cellular homeostasis. Chronic diseases, such as arthritis, lung disease and diabetes accelerate the aging of the cardiovascular system through persistent low-grade inflammation which occurs concomitant with changes in vascular shear leading to a disbalances physiological homeostasis. Under these circumstances shear force experienced by endothelial cells, dramatically changes. Endothelial cells monitored shear through mechanosensitive ion channels such as Piezo 1, which alters the vascular hormonal response. Endothelial cells from different vascular bed are exposed to a wide range of shear forces reflecting the shear experienced within large arteries down to post-capillary venules. Endothelial cells isolated from specific vascular beds also have memory of the shear that they developed under. Currently, most endothelial cell research is performed using static conditions, which is problematic as lack of shear drives a pathological phenotype. Designing new ways to assess endothelial cells under constant shear would help inform better treatments in the future.
External activity
We are grateful to our funders for their continued support of our work.
- Medical Research Foundation - Elucidation of new immunomodulatory pain pathways in young adults with long-term sensory neuronal activation after juvenile cancer treatment. (2024 - 2026)
- Ethics Application - Evaluating the aspirations and experiences of students on the foundation biology courses (2023)
- Physiology Society - Changes in immune cell physiology in asthma and cancer comorbidities (2022)
- Dianippon-Sumitomo - Development of a model to study the acute effects of cigarette smoking in man: a parallel in vivo and in vitro approach using multi-omics analysis (2012-2016)
- King Saud University - Understanding how Vioxx and other COX-2 inhibitors cause cardiovascular deaths (2011-2016)
- National Heat and Lung Institute (PhD Studentship) - Role of cyclooxygenase and associated lipid mediators in innate immune function of the lung (2011-2014)
- Medical Research Council - The Physiology, pharmacology and function of stem cell derived endothelial cells (2011-2014)
- British Heart Foundation - Understanding the role of Toll like receptors (TLRs) and interferon signalling in the endothelin-1 (2009-2012)
- National Heat and Lung Institute (PhD Studentship) - The role of the innate immune system receptor, TLR2 and its co-receptor partners in cell growth (2009-2012)
- Wellcome Trust - Role of TLR2 in the sensing of oxidants and ensuing inflammation: implications for therapeutic intervention (2008-2013)
- Royal Brompton Hospital and Harefield NHS Trust - Assessing the patterns of gene activation through Toll-like receptor 2 ligation by oxidants and classical TLR2 ligands in human endothelial cells versus monocytes (2006-2007)
- National Heat and Lung Institute (PhD Studentship) - Understanding the roles of the nuclear receptor PPARβ versus prostacyclin (IP) receptor in the anti-platelet effects of prostacyclin (2006-2009)
- British Lung Foundation - Sensing of oxidative stress by the innate immune system in inflammatory lung disease (2006-2008)
- NicOx - Effects of nitro-modified steroids as anti-thrombotic agents (2003-2004)
External Examiner for Pharmacology levels 4-6 University of Westminster (2022-2028)
Publications
Key Publications:
Valentine T, Hardowar L, Elphick-Ross J, Hulse RP, Paul-Clark M. The Role of Vascular-Immune Interactions in Modulating Chemotherapy Induced Neuropathic Pain. Front Pharmacol. 2022 Jun 22;13:887608. doi: 10.3389/fphar.2022.887608.
Parzych K, Zetterqvist AV, Wright WR, Kirkby NS, Mitchell JA, Paul-Clark MJ. Differential role of pannexin-1/ATP/P2X7 axis in IL-1β release by human monocytes. FASEB J. 2017 Jun;31(6):2439-2445. doi: 10.1096/fj.201600256.
Ross CL, Galloway-Phillipps N, Armstrong PC, Mitchell JA, Warner TD, Brearley C, Ito M, Tunstall T, Elkin S, Kon OM, Hansel TT, Paul-Clark MJ. Protocol for a human in vivo model of acute cigarette smoke inhalation challenge in smokers with COPD: monitoring the nasal and systemic immune response using a network biology approach. BMJ Open. 2015 Jan 28;5(1):e005750. doi: 10.1136/bmjopen-2014-005750.
Wright WR, Parzych K, Crawford D, Mein C, Mitchell JA, Paul-Clark MJ. Inflammatory transcriptome profiling of human monocytes exposed acutely to cigarette smoke. PLoS One. 2012;7(2):e30120. doi: 10.1371/journal.pone.0030120.
Paul-Clark MJ, McMaster SK, Sorrentino R, Sriskandan S, Bailey LK, Moreno L, Ryffel B, Quesniaux VF, Mitchell JA. Toll-like receptor 2 is essential for the sensing of oxidants during inflammation. Am J Respir Crit Care Med. 2009 Feb 15;179(4):299-306. doi: 10.1164/rccm.200707-1019OC.
Moraes LA, Paul-Clark MJ, Rickman A, Flower RJ, Goulding NJ, Perretti M. Ligand-specific glucocorticoid receptor activation in human platelets. Blood. 2005 Dec 15;106(13):4167-75. doi: 10.1182/blood-2005-04-1723.
Paul-Clark MJ, Van Cao T, Moradi-Bidhendi N, Cooper D, Gilroy DW. 15-epi-lipoxin A4-mediated induction of nitric oxide explains how aspirin inhibits acute inflammation. J Exp Med. 2004 Jul 5;200(1):69-78. doi: 10.1084/jem.20040566.
Dr Paul-Clark up-to-date list of publications is available to be viewed through his ORCID profile, and google scholar profiles.