The main aim of my lab is to investigate the role of the actin cytoskeleton in both platelet and megakaryocyte cell function. This involves the use of fluorescent, confocal and super resolution microscopy within both platelet spreading and thrombus formation assays. The main projects within the lab at present are:
Project 1: How is platelet inhibitory signaling altered by the vascular environment?
The vascular environment alters constantly throughout life. As the vascular environment changes it can then allow the formation of multiple different conditions, from diabetes, to dementia, and can also underlie vascular events such as stroke and heart attacks. A key cell within the blood, is the platelet.This cell is normally held in an inhibited state. However, as the vascular environment changes this inhibited state can alter. By altering the balance of activatory and inhibitory signaling, this then alters how likely platelets are to activate and form a thrombus. Understanding how platelet inhibition is corrupted by changes to the vascular environment is therefore key. This strand of research is completed alongside Dr Graeme Stasiuk, and Dr Monica Arman.
Project 2: Thrombiglow: 'Smart' Multimodal Platelet specific 'Theranostic' Drug Delivery Imaging Agents
This strand of research is completed in collaboration with Dr Graeme Stasiuk (King's College London). Anti-platelet therapy at present uses drugs that are non-specific and have side-effects on bleeding, and in the case of Aspirin, stomach ulceration. This research aims to use nanomaterials to design a drug therapy that would target platelets specifically, reduce side-effects such as bleeding, whilst maximising platelet inhibition, and so help to prevent thrombus formation.
Grants at present:
1) BHF PhD studentship (Co-PI) " Effect of hypoxia on prostacyclin-mediated inhibition of platelet function” (£110,353) 2022-2025 (with Dr Monica Arman (PI)). This project is a non-clinical PhD studentship that is in collaboration with Dr Monica Arman (PI). Tissue hypoxia occurs in multiple cardiovascular and pulmonary conditions including myocardial infarction, stroke, chronic obstructive pulmonary disease (COPD) and sleep apnoea. However, knowledge on how human platelets function in hypoxic (low oxygen) conditions is lacking. Our group is interested in understanding how hypoxia affects platelet inhibition, specifically endothelial-released prostacyclin (PGI2) and its downstream intracellular signalling.
2) MRC New Investigator Award (co-PI) “Matrix metalloproteinase activated Multimodal 'Theranostic' Drug Delivery Imaging Agents for thrombosis” (£679,625) 2020-2024 (With Graeme Stasiuk)This project will drive the development of a nanoparticle based stroke therapy. The nanoparticle is designed to bind the clot specifically to deliver the drug in a specific and directed manner, whilst also having optical capability to monitor clot dissolution.
3) BHF PhD studentship (PI) “Is Zinc critical for the control of platelet cyclic nucleotide signalling? (£108,240) 2019-2022. This project is a non-clinical PhD studentship funded to understand how the inhibitory signalling induced by the cyclic nucleotides, prostacyclin and nitric oxide, is changed by the presence or absence of zinc.
Present Lab Members
Leigh Naylor-Adamson: MRC funded PDRA
Charlie Coupland (PhD): BHF student 2019-2022
Zoe Booth (PhD): University of Hull studentship 2019-2022
Michelle Kinnon (PhD): BHF student 2017-2020 (PI Graeme Stasiuk)
Past lab Members:
Muhammad Yusuf: PhD awarded 2017
Lloyd Atkinson (PhD): PhD awarded 2018
Yusra Ahmed (PhD): PhD awarded 2021
1) MZ Yusuf, Z Raslan, L Atkinson, A Aburima, SG Thomas, KM Naseem, and SDJ Calaminus. Prostacylin reverses platelet spreading leading to instability of thrombus formation via cAMP mediated regulation of RhoA activity. Scientific Reports 2017
2) Sinclair A, Park L, Shah M, Drotar M, Calaminus S, Hopcroft L.E.M, Kinstrie R, Guitart A.V, Dunn K, Abraham S.A, Sansom O, Michie A.M, Machesky L, Kranc K.R, Graham G.J, Pellicano F, Holyoake T.L. cxcr2 and CXCR4 regulate survival and self-renewal of haematopoietic stem/progenitor cells. Blood, 2016. http://dx.doi.org/10.1182/blood-2015-08-661785
3) Schachtner H., Calaminus S.D.J., Thomas S.G., Machesky L.M. Podosomes in adhesion, migration, mechanosensing and matrix remodelling. Cytoskeleton, 2013.
4) Schachtner H., Calaminus S.D.J., Sinclair A., Moneypenny J., Blundell M., Thrasher A.J., Michie A., Vukovic M., Jones G.E., Thomas S.G., Watson S.P., Machesky L.M. Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane. Blood, 2013.
5) †Calaminus S.D.J., †Guitart A., †Sinclair A., Schachtner H., Watson S.P., Holyoake T.L., Kranc K.R., Machesky L.M. Lineage tracing of Pf4-Cre marks hematopoietic stem cells and their progeny. Plos One, 2012. (†Joint first authors)
6) Zech T., Calaminus S.D.J., Machesky L.M. Actin on Traffic. How actin controls receptor transport. Point of view article. Cell adhesion and Migration, 2012.
7) Schachtner H., Li A., Stevenson D., Calaminus S.D.J., Thomas S.G., Watson S.P., Sixt M., Wedlich-Soldner R., Strathdee D., Machesky L.M. Tissue inducible lifeact expression visualizes actin dynamics in vitro and in vivo. Experimental Cell Research 2012.
8) Zech T†., Calaminus S.D.J†., Caswell P., Spence H.J., Carnell M., Insall R.H., Norman J., Machesky L.M. The Arp2/3 activator WASH regulates a5b1 integrin mediated invasive migration. Journal of Cell Science Nov: 2011. (†Joint first authors)
9) Thomas S.G., Calaminus S.D.J., Machesky L.M., Alberts A.S., Watson S.P. G-protein coupled and ITAM receptor regulation of the formin FHOD1 through Rho Kinase in platelets. Journal of Thrombosis and Haemostasis. 2011 Aug;9(8):1648-51
10) Carnell M., Zech T., Calaminus S.D.J., Ura S., Hagedorn M., Johnston S., May R., Soldati T., Machesky L.M., Insall R.H. WASH-Dependent Actin Polymerization Causes Vesicle Neutralization and Exocytosis by Driving Removal of V-ATPase. Journal of Cell Biology 2011.
11) Calaminus S.D.J., Thomas S., McCarty O.J., Machesky L.M., Watson S.P. Identification of a novel actin rich structure, the actin nodule, in the early stages of platelet spreading. Journal of Thrombosis Haemostasis. 2008.
12) Thomas S.G., Calaminus S.D.J., Auger J.M., Watson S.P., Machesky L.M. Studies on the actin-binding protein HS1 in platelets. BMC Cell Biology. 2007.
13) Tomlinson M.G., Calaminus S.D.J., Berlanga O., Auger J.M., Bori-Sanz T., Meyaard L., Watson S.P. Collagen promotes sustained glycoprotein VI signalling in platelets and cell lines. Journal of Thrombosis and Haemostasis. 2007.
14) * Calaminus S.D.J., Auger J.M., McCarty O.J.T., Wakelam M.J.O., Machesky L.M., Watson S.P. Myosin II is required for platelet structure during spreading, and is required for thrombus stability. Journal of Thrombosis and Haemostasis. 2007.
15) Calaminus S.D.J., McCarty O.J.T., Auger J.M., Insall R.H., Watson S.P., Machesky L.M. A major role for Scar/WAVE-1 downstream of GPVI in platelets. Journal of Thrombosis and Haemostasis. 2007.
16) Pearce A.C., McCarty O.M.J., Calaminus S.D.J., Turner M., Vigorito E., Watson S.P. Vav family proteins are required for optimal regulation of PLCgamma2 by integrin alphaIIbbeta3. Biochemical Journal. 2007.
17) McCarty O.J.T., Calaminus S.D.J., Berndt M.C., Machesky L.M., Watson S.P. Von Willebrand factor mediates platelt spreading through glygoprotein ib and aiibb3 in the presence of botrocetin and ristocetin, respectively. Journal of Thrombosis and Haemostasis. 2006.
18) Pettitt T.R., Dove S.K., Lubben A., Calaminus S.D.J., Wakelam M.J.O. Analysis of intact phosphoinositides in biological samples. Journal of Lipid Research 2006.
* Awarded 2007 Journal of Thrombosis and Haemostasis young scientist paper of the year