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Title: The biogenesis of Weibel-Palade bodies
Author: Zenner, Helen Laura
ISNI:       0000 0004 2671 3922
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2007
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Weibel-Palade bodies (WPB) are the secretory lysosome-related organelles (LRO), of endothelial cells. The storage of both P-selectin and von Willebrand factor in the WPB means the organelles play key roles in both inflammation and haemostasis respectively. The storage of the VWF as tubules is responsible for the unique elongated shape of WPB, and, in turn, the organisation as tubules is essential to its release as functional platelet binding strings upon stimulation. Whilst the functional importance of VWF tubulation is thus clear, the relationship between tubules and biogenesis has not been studied. This relationship has been investigated using the relatively new technique of high pressure freezing (HPF) and freeze substitution (FS) followed by electron microscopy to consider biogenesis at the ultrastructural level. Use of this technique indicates that tubules are able to form within the trans-Golgi network (TGN). The WPB then remain attached to the TGN by a membranous stalk and become filled with tubules. The VWF tubules in the immature WPB are disordered but during maturation there is a dramatic increase in the spatial organisation of the tubules and in organelle electron density. Another maturation step the WPB undergo is removal of unwanted material, indicated by the presence of clathrin-coated buds on the WPB. Additionally, the use of HPF-FS has raised questions concerning the role of the cytoskeleton in the formation of WPB and the machinery required for the scission of the WPB from the TGN. Preliminary experiments indicate that the actin cytoskeleton, Myosin VI, FAPP and dynamin may be involved in the biogenesis at the TGN. Finally, since the WPB are described as LROs, it seems possible that a similar machinery may be involved in their biogenesis to other LROs. Hermansky-Pudlak syndrome (HPS) is an example of disease that affects LROs. The symptoms of the patients can be explained by defects in melanosome and platelet dense granules respectively. However, knocking down the HPS proteins that form the biogenesis of lysosome-related organelles complexes (BLOC) two and three in endothelial cells has no effect on the biogenesis of WPB.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available