MRC National Institute for Medical Research, London
Science for Health
This project is now closed
Molecular regulation of Weibel Palade body fusion and fusion pore dynamics
Project supervisor: Tom Carter (Physical Biochemistry)
Vascular endothelial cell (EC) dysfunction is implicated in important diseases (e.g. diabetes, hypertension, infection, cancer), while defects in the secretory pathway and membrane trafficking underlying a host of human disorders (Aridor et al, 2000; Aridor et al, 2002). Our lab focuses on the secretory pathway of ECs with the aim of understanding how ECs regulate and co-ordinate the storage, trafficking and secretion of coagulant, inflammatory and angiogenic molecules directly implicated in human health and disease.
ECs contain a single pool of regulated secretory organelles, the Weibel Palade bodies (WPBs), responsible for storing and releasing von Willebrand factor and a host of other molecules, many with opposing biological functions. Recently (Babich et al, 2008) we have shown that WPBs do not simply discharge their contents indiscriminately upon exocytosis but instead selectively control which molecules are released or retained. The key to this process appears to be the control over the fusion pore that forms and connects the lumen of the WPB and the extracellular space. Thus, EC may be able to discriminate and control different cellular processes by selective release of cargo molecules from a single secretory granule population. How different states of EC activation translate into distinct fusion pore dynamics and cargo release remain unclear, as does the molecular basis for the control of the WPB fusion pore.
This project will explore the molecular basis for the control of WPB fusion pore dynamics in response to Ca stimulation under different states of ECs activation. Combined high speed live cell fluorescence imaging and electrochemical approaches, already established in the lab, will be used to resolve the formation and dynamics of the WPB fusion pore. Molecular and cell biological approaches will be used to investigate the role of identified candidate molecules (proteins and lipids) in the modulation of WPB fusion pore dynamics.
References
- Aridor, M and Hannan, LA (2000)
Traffic jam: a compendium of human diseases that affect intracellular transport processes.
Traffic 1, 836-851 PubMed abstract - Aridor, M and Hannan, LA (2002)
Traffic jams II: an update of diseases of intracellular transport.
Traffic 3, 781-790 PubMed abstract - Babich, V; Meli, A; Knipe, L; Dempster, JE; Skehel, P; Hannah, MJ and Carter, T (2008)
Selective release of molecules from Weibel Palade bodies during a lingering kiss.
Blood 111, 5282-5290 PubMed abstract
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