Professor Tom Carter’s research is aimed at identifying the molecular mechanisms that control the regulated secretion of coagulant and inflammatory mediators from vascular endothelial cells.
Endothelial cells line the lumen of all blood vessels and together constitute one of the largest and most complex secretory organs in the body. Endothelial cells control vital physiological processes such as blood flow, blood clotting, inflammation, vessel growth and wound healing through the secretion of a variety of coagulant, inflammatory and angiogenic molecules. Endothelial cell dysfunction alters the balance of secreted molecules and increases the risk of hypertension, ischemia, stroke, heart attack, infection and cancer. The mechanisms controlling the synthesis, packaging, trafficking and secretion of molecules in endothelial cells represent targets for modifying endothelial cell function in health and disease. Professor Carter’s group’s goal is to understand how endothelial cells secrete mediators directly implicated in human health and disease under “normal” and “perturbed” conditions. A better understanding of the basic cellular processes by which endothelial cells function will translate into novel therapeutic agents for human medicine.
Professor Carter’s current work focuses on the biology of Weibel-Palade bodies (WPBs), the main regulated secretory granule of endothelial cells. WPBs contain von Willebrand factor, a pro-coagulant and adhesive molecule that plays a vital role in haemostasis.
Professor Carter’s current work comprises three interrelated strands of research which address the following questions:
- How is the transport, exocytosis and recycling of WPBs in endothelial cells controlled and regulated?
- What are the structural changes in von Willebrand Factor and WPBs during granule maturation, export and secretion?
- How is WPB fusion pore opening and closing regulated and controlled?
The group’s work is funded by a Medical Research Council programme grant (2012-2018).
Tom Carter graduated from King's College London in 1986 with a joint honors degree in Physiology and Pharmacology and then carried out research for a PhD in Pharmacology in the group of Professor Jeremy Pearson in the Vascular Biology Unit of the MRC Clinical Research Center in Harrow, London.
His PhD work established a crucial role for intracellular calcium as the major trigger for the synthesis of prostacyclin (a potent vasodilator and anti-platelet mediator) during purinoceptor-activation in human endothelial cells. In 1989 he moved to the laboratory of Dr David Ogden in the Division of Neurophysiology at the MRC National Institute for Medical Research (NIMR) to learn and apply whole cell patch clamp, fluorescence photometry and flash photolysis techniques. Here he studied the mechanisms that underlie the generation of hormone-evoked calcium signals in endothelial cells and established the use of novel caged nitric oxide donors for the quantitative investigation of nitric oxide action in vascular tissues.
In 1995 he was awarded a British Heart Foundation Gerry Turner Fellowship and in 1998 a British Heart Foundation Basic University Lectureship. In 1998 he moved from the NIMR to join the Pharmacology Department at University College London as a lecturer and an honorary lecturer in Clinical Pharmacology. In 2003, he returned to NIMR, to take up a Career Scientist position within the Division of Molecular Neuroendocrinology where he concentrated on developing and applying new tools for high resolution, high speed, multicolour imaging of the intracellular trafficking and exocytosis of individual secretory granules in living endothelial cells.
In 2009 he became Acting Head of the Division of Molecular Neuroendocrinology and in 2010 became a Principle Investigator in the Division of Physical Biochemistry at NIMR. In October 2013 he joined the Division of Biomedical Sciences at St George's University of London as Professor of Endothelial Cell Biology. In 2016 he became head of the Cell Biology & Genetics research center at St George's University, and was elected a Fellow of the Royal Society of Biology (FRSB).
For reprints see the St George's Online Research Archive (SORA).
Knipe L, Meli A, Hewlett L, Bierings R, Dempster J, Skehel P, Hannah MJ, Carter T (2010). A revised model for the secretion of tPA and cytokines from cultured endothelial cells. Blood, 116:2183-2191. PMID 20538801
Bierings R, Hellen N, Kiskin N, Knipe L, Fonseca AV, Patel B, Meli A, Rose M, Hannah MJ, Carter T.(2012). The interplay between the Rab27A effectors Slp4 a and MyRIP controls hormone-evoked Weibel-Palade body exocytosis. Blood, 120: 2757-2767. PMID22898601
Cookson EA, Conte IL, Dempster J, Hannah MJ, Carter T. (2013). Characterisation of Weibel-Palade body fusion by amperometry in endothelial cells reveals fusion pore dynamics and the effect of cholesterol on exocytosis. J Cell Sci. 126:5490-5499. PMID24127569
Dorothee van Breevoort, Ambrosius P. Snijders, Nicola Hellen, Sarah Weckhuysen, Kathinka W.E.M. van Hooren, Jeroen Eikenboom, Karine Valentijn, Mar Fernandez-Borja, Berten Ceulemans, Peter De Jonghe, Jan Voorberg, Matthew Hannah, Tom Carter and Ruben Bierings (2014). STXBP1 promotes Weibel-Palade body exocytosis through its interaction with the Rab27A effector Slp4-a. Blood, 123:3185-94.PMID24700782
Conte IL, Cookson EA, Hellen N, Bierings R, Mashanov, G, Carter T. (2015). Is there more than one way to unpack a Weibel-Palalde body? Blood, 126:2165-7. PMID: 26377598
Conte IL, Hellen N, Bierings R, Mashanov GI, Manneville JB, Kiskin NI, Hannah MJ, Molloy JE, Carter T.(2016). Interaction between MyRIP and the actin cytoskeleton regulates Weibel-Palade body trafficking and exocytosis. J Cell Sci. [Epub ahead of print]. PMID: 26675235
Erent M, Meli A, Moisoi N, Babich V, Hannah MJ, Skehel P, Knipe L, Zupancic G, Ogden D, Carter T (2007). Rate, extent and concentration dependence of histamine-evoked Weibel-Palade body exocytosis determined from individual fusion events in human endothelial cells. J Physiol, 583:195-212. PMID 17540703.
Babich V, Meli A, Knipe L, Dempster JE, Skehel P, Hannah MJ, Carter T. (2008). Selective release of molecules from Weibel Palade bodies during a lingering kiss. Blood, 111:5282-5290. PMID 18252862 (Plenary paper).
Berriman JA, Li S, Hewlett LJ, Wasilewski S, Kiskin FN, Carter T, Hannah MJ, Rosenthal PB (2009). Structural organization of Weibel-Palade bodies revealed by cryo-EM of vitrified endothelial cells. Proc Natl Acad Sci U S A, 106:17407-17412. PMID 19805028
Dr Ianina Conte (postdoctoral research scientist). Project: Molecular basis for the Weibel Palade body trafficking and exocytosis.
Ms Camille Lenzi (postgraduate research student). Project: Molecular basis for calcium-regulated Weibel-Palade body exocytosis.
Dr Katalin Török (St George's Cell Biology and Genetics Research Centre). Calcium signalling, Genetically encoded calcium indicators.
Dr Dan Osborn (St George's Cell Biology and Genetics Research Centre).
Dr Justin Molloy (Crick Institute, Mill Hill Laboratory, London) Molecular motors and single molecule imaging.
Dr Peter Rosenthal, (Crick Institute, Mill Hill Laboratory, London) Structural studies of endothelial cells and their secretory granules.
Dr David Ogden (Universite Paris Descartes, Paris) Flash photolysis and exocytosis.
Dr Gregor Zupancic Dr Gregor Zupancic (European Patent Office, the Hague) Statistical analysis of the kinetics of secretory granule exocytosis.
Dr Paul Skehel (Center for Intergrative Physiology, University of Edinburgh) P-selectin trafficking and secretion.
Dr John Dempster (University of Strathclyde) Development of imaging and electrophysiology software and instrumentation.
Professor Caroline Wheeler-Jones (Royal Veterinary College, London) Prostaglandin synthesis and release.
Dr Guy Moss (Div Neuroscience, Physiology and Pharmacology, UCL, London) Ion conductance scanning microscopy and single secretory granule patch clamp.
Professor Marlene Rose (Imperial College, London) Secretion in adult human microvascular endothelium.
Dr Matthew Hannah (Microbiology Services Division, Colindale, Public Health England, London) EM and cell biology of secretory pathway.
Dr Ruben Bierings (Department of Plasma Proteins, Sanquin Research, Amsterdam) Mechanisms of Weibel-Palade body trafficking and exocytosis.
Dr Jean-Baptiste Manneville (Institute Curie, Subcellular Structure & Cellular Dynamics) Mechanisms of Weibel-Palade body trafficking and exocytosis.
Professor Carter and colleagues' research has been funded by grants and fellowships from the British Heart Foundation, the Medical Research Council, NATO and the British Council.
Current Funding: 2013-2018 Medical Research Centre programme grant (St George's).