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Title: Tissue factor induction and regulation in monocytes
Author: McIlroy, Justine Marie
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1999
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Tissue factor (TF; CD142) is the principal initiator of the coagulation cascade. This 45kDa protein is constitutively expressed in extravascular cells and as such forms a protective haemostatic envelope surrounding the vasculature ready to initiate coagulation on vascular injury. When bound to its cofactor factor VII/VIIa in the normal bloodstream, it forms a highly catalytic complex (TF/VIIa) which triggers the activation of factors IX and X and ultimately the formation of a fibrin clot. Peripheral blood cells do not, in a resting state, express TF allowing maintenance of the fluidity of the blood. However, agonists such as bacterial lipopolysaccharide (LPS) and immune complexes, if present in the bloodstream can induce the expression of TF on monocytes resulting in activation of the clotting process. This induction of Monocyte TF has been clearly implicated in the pathology of various disease processes such as disseminated intravascular coagulation (DIC) following endotoxaemia, thromboembolic disease and atherosclerosis. We have characterised a whole blood model to investigate the induction of TF on monocytes, and have developed a highly specific and sensitive flow cytometric technique to measure the TF protein on the cell surface of activated monocytes. We have shown that there is a reproducible dose dependent induction of TF on monocytes in whole blood by LPS (10pg/ml-100μg/ml) after a 2 h incubation. Antisense therapy is aimed at the specific inhibition of a particular target protein by preventing the translation of its mRNA. Antisense (AS) oligodeoxynucleotides (ODNs) are short single stranded lengths of reverse complementary DNA which can be designed to specifically hybridise to a target mRNA, through Watson and Crick base pairing laws, arresting translation of the protein. We have investigated the potential of antisense therapy to inhibit specifically the nascent induction of TF in monocytes in response to LPS. We have characterised the uptake kinetics of a fluorescently labelled 25 base phosphorothioate oligonucleotide into peripheral blood monouclear cell (PBMC) subtypes. We have shown that the uptake of GEM(R)91 is dose and time dependent and is not saturated at concentrations of up to 10μM for 4 hours.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available