Thesis Marije Kat

On 1 April 2022 Sanquin researcher Marije Kat defended her thesis 'The Weibel-Palade body from formation to fireworks' at the University of Amsterdam.

Promotor: Prof J Voorberg PhD
Copromotores: R Bierings PhD and Coert Margadant PhD
Venue: Aula - Oude Lutherse kerk, University of Amsterdam

Summary

The inner lining of the vasculature is composed of a monolayer of endothelial cells (ECs), forming a dynamic barrier at the interface of the blood and the underlying tissue. In the frontline, ECs need to adequately respond to stress signals, ensure hemostasis, and regulate immune responses and angiogenesis. For this purpose they make the Weibel-Palade body (WPB): a unique, rod-shaped secretory granule that stores hemostatic, inflammatory and angiogenic mediators, which can be rapidly released into the blood upon vascular injury. The main component Von Willebrand Factor (VWF) is a large multimeric protein that plays a central role in hemostasis, and is required for WPB biogenesis. When secreted upon stimulation VWF multimers unwind, forming adhesive strings to catch platelets and promote thrombus formation. Qualitative or quantitative defects in VWF can lead to the bleeding disorder Von Willebrand’s disease (VWD). In this thesis we have studied the regulatory processes involved in WPB formation and trafficking and their impact on VWF secretion. The immunofluorescent imaging of VWF from formation until secretion exposes remarkable snapshots, reminiscent of microscopic fireworks, which have been the inspiration for the title.

Chapters

Chapter 1
General introduction

Chapter 2
Exocytosis of Weibel-Palade bodies: How tounpack a vascular emergency kit Abstract

Chapter 3
Alternative trafficking of Weibel-Palade body in CRISPR/Cas9-engineered von Willebrand factor-deficient blood outgrowth endothelial cells Abstract

Chapter 4
Syntaxin 5 determines Weibel-Palade body size and Von Willebrand factor secretion by controlling Golgi architecture Abstract

Chapter 5
GDP/GTP exchange factor MADD drives activation and recruitment of secretory Rab GTPases to Weibel-Palade bodies Abstract

Chapter 6
NBEAL2 mutations do not impact Weibel-Palade body biogenesis and exocytosis in Gray Platelet Syndrome endothelial cells

Chapter 7
Dispatch and delivery at the ER - Golgi interface: how endothelial cells tune their hemostatic response

Chapter 8
General Discussion

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Download PhD thesis (university repository)

Thesis Marije Kat