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Creation of modified heparins to probe platelet-endothelial glycocalyx interactions necessary for inflammation.
Closing date
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Supervisors
Dr Simon Pitchford , simon.pitchford@kcl.ac.uk, Senior Lecturer in Pharmacology, King’s College London
Project Details

This ambitious project at King’s College London (KCL) aims to elucidate how platelets prepare the surface of the vascular endothelium (glycocalyx) for leukocyte adhesion, and to gain an understanding of the surface chemistry by which heparin can interfere with this process, as a basis for the anti-inflammatory properties of heparin. These interactions are highly relevant since the modification of the pulmonary endothelial glycocalyx has been observed during lung injury arising from infection, for example in patients suffering from COVID-19.

Platelets play a critical role in innate immunity; being recruited independently of other cell types, yet are also essential for efficient leukocyte recruitment to inflamed or infected lungs. Mechanisms by which platelets adhere and ‘prepare’ the surface of the respiratory endothelium for leukocyte recruitment require greater understanding, because the luminal side of the endothelium is coated by a glycocalyx structure that normally acts as a barrier to these circulating cells. Significantly, platelet-dependent leukocyte adhesion to endothelium can be inhibited by non-anticoagulant heparins, which are highly sulfated glycosaminoglycans (GAG).  Uniquely as a circulating cell, platelets contain the CXC chemokine Platelet Factor4 (PF4, CXCL4), which binds with high affinity to heparin,  and to negatively charged cell surface GAGs (for example heparan sulfate) of the glycocalyx. However, the role of PF4 in platelet preparation of the glycocalyx for leukocyte recruitment, and an understanding of the surface chemistry by which heparin can interfere has not been examined. Our project partners at The National Institute for Biological Standards and Control (NIBSC), have a unique panel of non-anticoagulant modified heparins and related polysaccharides that have anti-inflammatory properties, and through the use of these compounds as experimental tools, this lack of understanding can be addressed. Ultimately, this knowledge will in the future lead to the development of a novel class of anti-inflammatory drug to be used during infections, but with a greater efficacy and safety profile compared to current clinical anticoagulant heparin.

 

WORK PROGRAMME:

This 4 year PhD project will be conducted at the Sackler Institute of Pulmonary Pharmacology at King’s College London under the supervision of Dr Simon Pitchford and Prof Clive Page. This team has led the international research field in investigating the roles of platelets during inflammation and trauma, which are recognisably distinct pathologies from the well-recognised roles of platelets during haemostasis and events leading to thrombosis. The student will use techniques in pharmacology /physiology (in vitro and in vivo functional assays) to investigate platelet-endothelial cell interactions, and this will be enhanced using state-of-the-art microscopy techniques (stochastic optical resolution microscopy - STORM), electron microscopy (EM), and analytical structural chemistry approaches. A 6 month placement (NIBSC) under the supervision of Dr John Hogwood, Professors Elaine Gray and Barbara Mulloy (World-renowned experts in heparin science) will then enable the student to prepare modified heparins and learn physico-chemical and biological assays for their characterisation, and  measurement of PF4 and heparin interactions. Thus, the placement interconnects with the deliverables of the overall project objectives at KCL and the research remit of NIBSC. This will provide the student with an exciting PhD experience of research in very different and inspiring environments, bringing a truly interdisciplinary approach to a highly topical subject.

References

Cleary SJ et al. LPS-induced lung platelet recruitment occurs independently of neutrophils, P-selectin, and PSGL-1. Am J Respir Cell Mol Biol. 2019; 61: 232-243. doi: 10.1165/rcmb.2018-0182OC.

Nguyen Q & Shiva S. Platelets: Lone rangers of inflammatory signalling in the lung. Am J Respir Cell Mol Biol. 2019; 61: 139–140. doi: 10.1165/rcmb.2019-0057ED

Riffo-Vasquez Y et al. A non anti-coagulant fraction of heparin inhibits leukocyte diapedesis into the lung by an effect on platelets. Am J Respir Cell Mol Biol. 2016; 55: 554-563. doi: 10.1165/rcmb.2015-0172OC.

Pitchford SC et al. Platelets in neutrophil recruitment to sites of inflammation. Curr Opin Hematol. 2017; 24:23-31. doi: 10.1097/MOH.0000000000000297.

Endothelial Injury and Glycocalyx Degradation in Critically Ill Coronavirus Disease 2019 Patients: Implications for Microvascular Platelet Aggregation. Crit Care Explor. 2020: 2; e0194. doi: 10.1097/CCE.0000000000000194.

Hogwood J et al. Heparin and Non-Anticoagulant Heparin Attenuate Histone-Induced Inflammatory Responses in Whole Blood. PLoS One. 2020; 15: e0233644. doi: 10.1371/journal.pone.0233644.

Mulloy B et al. Pharmacology of Heparin and Related Drugs. Pharmacol Rev. 2016;68:76-141. doi: 10.1124/pr.115.011247.

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