Professor of Old Age Psychiatry
Senior Lecturer in Nanomaterials and Biointerfaces
Professor of Diabetes and Metabolic Medicine
Professor of Vascular Physiology
Director, Ageing Research at King's
Hypoxia and Physiological Oxygen in the Brain
The understanding the mechanisms regulating neurovascular redox defenses are key for improved clinical translation for stroke and age-related neurodegenerative conditions. Our previous studies in a rodent model of ischemic stroke established that activation of Nrf2 defense enzymes by treatment with dietary phytochemicals afford protection against neurovascular and neurological deficits. We now investigate the actions of potential therapeutic compounds and phytochemicals on antioxidant defence pathways in mouse and human brain microvascular endothelial cells adapted long-term to normoxic and hypoxic oxygen levels to assess the mechanisms by which they confer protection under physiological oxygen levels.
Metals in Hypoxia / Reoxygenation
We are investigating the mechanisms by which changes in intracellular metals contribute to human coronary artery endothelial and smooth muscle cell injury following ischaemia and reperfusion using novel metallomic analytical methods in collaboration with the London Metallomics Facility through funding from Heart Research UK. Cells are adapted long-term to normoxic (5 kPa) and hypoxic (1 kPa) oxygen levels to assess whether perturbations in redox signalling pathways alter the metallomic profile.
Microfluidics in Physoxia and Hypoxia
Vascular cells are continually exposed to biomechanical forces including fluid shear stress (FSS) and cyclic stretch. We are using 3D-microfluidic chip platforms to culture arterial, venous and microvascular endothelial cells under defined FSS within physiological oxygen environments to better recapitulate the in vivo environment to further understand the importance of mechanotranduction in vascular health, ageing and the pathology of cardiovascular diseases for clinical translation and drug descovery.
Sevimli G, Smith MJ, Caglar TA, Bilirc S, Secilmis M, Altuna HY, Yigit EN, Yang F, Keeley TP, Malli R, Öztürk G, Mann GE, Eroglu E (2022) Nitric oxide biosensor uncovers diminished ferrous iron-dependency of cultured cells adapted to physiological oxygen levels Redox Biol. 53: doi: 10.1016/j.redox.2022.102319
Sies H, Belousov VV, Chandel NS, Davies MJ, Jones DP, Mann GE, Murphy MP, Yamamoto M, Winterbourn C (2022) Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology. Nat Rev Mol Cell Biol. doi: 10.1038/s41580-022-00456-z
Warpsinski G, Smith MJ, Srivastava S, Keeley TP, Siow RC, Fraser PA, Mann GE (2020) Nrf2-regulated redox signaling in brain endothelial cells adapted to physiological oxygen levels: Consequences for sulforaphane mediated protection against hypoxia-reoxygenation. Redox Biol. 37:101708.
Keeley TP, Mann GE (2019) Defining Physiological Normoxia for Improved Translation of Cell Physiology to Animal Models and Humans. Physiol Rev. 99:161-234.
Keeley TP, Siow RC, Jacob R, Mann GE (2018) Reduced SERCA activity underlies dysregulation of Ca2+ homeostasis under atmospheric O2 levels. FASEB J. 32:2531-2538.
Keeley TP, Siow RC, Jacob R, Mann GE (2017) A PP2A-mediated feedback mechanism controls Ca2+dependent NO synthesis under physiological oxygen. FASEB J. 31:5172-5183.
Chapple SJ, Keeley TP, Mastronicola D, Arno M, Vizcay-Barrena G, Fleck R, Siow RC, Mann GE (2016) Bach1 differentially regulates distinct Nrf2-dependent genes in human venous and coronary artery endothelial cells adapted to physiological oxygen levels. Free Radic Biol Med. 92:152-162.
Kumar A, Dailey LA, Swedrowska M, Siow RC, Mann GE, Vizcay-Barrena G, Arno M, Mudway IS, Forbes B (2016) Quantifying the magnitude of the oxygen artefact inherent in culturing airway cells under atmospheric oxygen versus physiological levels. FEBS Lett. 590:258-269.
El-Alami M, Viña-Almunia J, Gambini J, Mas-Bargues C, Siow RC, Peñarrocha M, Mann GE, Borrás C, Viña J (2014) Activation of p38, p21, and NRF-2 mediates decreased proliferation of human dental pulp stem cells cultured under 21% O2. Stem Cell Reports. 3:566-573.
Our second online symposium with London Metallomics Facility and Ageing Research at King's (ARK) highlighted the roles that metals play in normal brain function and disease, including recent developments in interventions for treatment of neurodegenerative diseases, the significance of redox signalling, and the recent advances in bioimaging technology to underpin these important scientific questions. The symposium featured speakers from Faculty of Life Sciences & Medicine and Institute of Psychiatry, Psychology & Neuroscience at King's, University College London, University of Warwick and Albert Einstein College of Medicine, USA. The keynote lecture given by Prof Costantino Iadecola, Weill Cornell Medicine, USA was on ‘Innate and adaptive immunity in stroke and dementia: challenges and opportunities'.
The field of metallomics utilises analytical tools to understand the biological roles of metals in biological space and time using elemental mass spectrometry. The characteristic metallomes change within the life span of cells and tissues. Our current research associated with the London Metallomics Facility (LMF) focuses on applications of metal profiling in brain and cardiovascular system, exploiting our Physiological Oxygen Lab to investigate metal profiles of cells grown under defined O2 concentrations. Together with the LMF, we will celebrate a King's Together Award with a virtual symposium including keynote speakers: Prof Sir Peter Ratcliffe FRS, Clinical Director, Francis Crick Institute and 2019 Noble Laureate in Physiology or Medicine for "discoveries of how cells sense and adapt to oxygen availability", and Prof Fiona Watt FRS, Executive Director, Medical Research Council.
HypoxEU Forum
The HypoxEU forum disseminates discoveries in responses to variations in cellular and tissue oxygenation. The second HypoxEU forum on 9 December 2021 brought together international researchers as a platform for sharing and connecting through their passion for oxygen research. The forum is supported by Baker-Ruskinn and their academic network.
HypoxEU forum on oxygenation and biology