Tom Nightingale completed his undergraduate studies at the University of Bath (M.biochem) and obtained his Phd at the University of Oxford. Subsequently Tom worked with Prof Daniel Cutler at the Laboratory for Molecular and Cellular Biology at University College London and joined the Centre for Microvascular Research at the WHRI in 2013. Tom is establishing his own research group to investigate the effect of intracellular trafficking of endothelial cell adhesion molecules on leukocyte extravasation.
Summary of Research
Research in my lab centres on the cell biology of endothelial cells during injury and inflammation.
Currently, two projects are running in the laboratory:
1. Trafficking of endothelial tight junction proteins during inflammation
Leukocyte recruitment from the blood vascular to infected tissues is a crucial part of the normal inflammatory response and allows clearance of pathogens from the affected area. However in some situations inappropriate and excessive recruitment of leukocytes can result in chronically inflamed tissues. The control of this process is therefore central to a normal resolution of an inflammatory situation.
The blood vascular endothelium plays a key part in this process as a number of endothelial cell surface receptors such as P- and E-selectin, CD31 and the Junctional Adhesion Molecules (JAMs) have important roles in the recruitment and transmigration of leukocytes through blood-vessel walls. Some of these adhesion receptors such as Jam-C are known to undergo intracellular trafficking and are found on intracellular vesicles and non-junctional plasma membrane following certain stimuli. My research centres on the mechanisms and machinery required for this intracellular trafficking and the subsequent impact on transmigration of leukocytes through the endothelial cell layer.
Figure 1: An activated endothelial cell. Von Willebrands factor (Red) Phalloidin (Green) and pan non-muscle myosin II (Blue)
2. An investigation into novel regulatory mechanisms for Von Willebrand factor secretion from endothelial cells
The response to vascular injury or infection is fast; this minimises loss of blood and spread of pathogens. As such, endothelial cells harbour specialised rod shaped storage organelles (WPB) that contain multiple pre-made pro-inflammatory and pro-haemostatic proteins. Within minutes of endothelial cell stimulation WPB are exocytosed and release their stored content into the vasculature thus starting the processes of both haemostasis and leukocyte recruitment. The most important haemostatic component of WPB is the glycoprotein VWF that comprises 90% of stored protein. Upon exocytosis these tubules are unfurled by the shear force present in the blood vasculature to produce millimetre-long protein strings revealing multiple binding sites for platelets. Failure to secrete properly processed VWF either due to mutation of the protein itself or due to defects in cellular machinery associated with WPB formation result in bleeding (Von Willebrands disease). Conversely, a failure to appropriately remove VWF from the blood stream due to an inactivity or absence of the shear dependent metalloprotease ADAMSTS13, results in thrombotic thrombocytopenic purpura, a syndrome that is typified by multiple microvascular occlusions. These two syndromes additionally serve to highlight the importance of VWF in cardiovascular disease and stroke. Animal models and patients with VWF disease exhibit a decreased incidence of atherosclerosis. Conversely patients with elevated levels of VWF have an increased risk of major cardiac events and stroke.
We are investigating novel means to regulate VWF secretion that are controlled by an actomyosin ring. By understanding this mechanism we hope, in the long term, to develop novel strategies for limiting cardiovascular disease and stroke.
Fellowships and awards
• Early Career Research Fellowship (2013)
• MRC New Investigator grant (2015
• BHF project grant (2016)
• WHRI Cofund fellowship for Katja Kostelnik (2016)
Members of the Group
Researcher/Staff: Dr Katja Kostelnik, Dr Christopher Robinson and Tom Mitchell
For a full list of publist publications click here
Stevenson NL, White IJ, McCormack JJ, Robinson C, Cutler DF, Nightingale TD. Clathrin-mediated post-fusion membrane retrieval influences the exocytic mode of endothelial Weibel-Palade bodies. J Cell Sci. 2017 Aug 1;130(15):2591-2605. doi: 10.1242/jcs.200840.
Nightingale TD, Cutler DF. (2013) The secretion of Von Willebrand Factor from endothelial cells; an increasingly complicated story. J.Thromb. Haemostasis.Jun;11 Suppl 1:192-201
Nightingale TD, Cutler DF, Cramer LP. (2012) Actin coats and rings promote regulated exocytosis.Trends Cell Biol. 22(6) p329-37.
Nightingale TD, White IJ, Doyle EL, Turmaine M, Harrison-Lavoie KJ, Webb KF, Cramer LP, Cutler DF. (2011) Actomyosin II contractility expels von Willebrand factor from Weibel-Palade bodies during exocytosis. J Cell Biol.194(4) p613-29.
Rojo Pulido I, Nightingale TD, Darchen F, Seabra MC, Cutler DF, Gerke V. (2011) Myosin Va acts in concert with Rab27a and MyRIP to regulate acute von-Willebrand factor release from endothelial cells. Traffic 12 (10) p1371-82
Michaux G, Dyer CE, Nightingale TD, Gallaud E, Nurrish S, Cutler DF. (2011) A role for Rab10 in von Willebrand factor release discovered by an AP-1 interactor screen in C. elegans.J.Thromb. Haemostasis 9 (2) p392-401
Nightingale TD, Pattni K, Hume AN, Seabra MC, Cutler DF. (2009) Rab27a and MyRIP regulate the amount and multimeric state of VWF released from endothelial cells. Blood113(20), p5010-18.
Nightingale TD, Frayne ME, Clasper S, Banerji S, Jackson DG. (2009) A mechanism of sialylation functionally silences the hyaluronan receptor LYVE-1 in lymphatic endothelium. J. Biol. Chem. 284(6), p3935-45.
Lui-Roberts WW, Ferraro F, Nightingale TD, Cutler DF.(2008) Aftiphilin and gamma-synergin are required for secretagogue sensitivity of Weibel-Palade bodies in endothelial cells. (2008) Mol. Biol. Cell. 19(12): p5072-81.
Metcalf DJ, Nightingale TD, Zenner HL, Lui-Roberts WW, Cutler DF. Formation and function of Weibel-Palade bodies. (2008) J. Cell. Sci. 121(Pt 1): p19-27.