Date Thursday October 8^th, 2009 from 13:00 hr to 14:00 hr

Location: Groene Zaal, UNS 50- 0.406

Name invited speaker: John H. Griffin

The Scripps Research Institute, La Jolla, CA, USA

Lecture: Mutagenic Dissection of Activated Protein C’s Multiple Activities

Moderator: Tilman M. Hackeng, department Biochemistry

+

Master Class (from 15:00-17:00) room 4.324A

Register with Dr. Gerry Nicolaes: This e-mail address is being protected from spambots. You need JavaScript enabled to view it

“…..Administration of activated protein C (APC) reduces mortality in severe sepsis patients, provides neuroprotective activities in various murine brain injury models, and has multiple beneficial effects in a variety of animal injury models.  APC exerts anticoagulant activities via inactivation of factors Va and VIIIa and cytoprotective activities via EPCR and PAR1.  APC mutants with selectively altered and opposite activity profiles, i.e., greatly reduced anticoagulant activity or greatly reduced cytoprotective activities, have been designed and prepared using site-directed mutagenesis.  Such APC mutants with distinctive activity profiles, namely cytoprotective-selective or antithrombotic selective activity profiles, have been used to delineate the relative importance of APC’s cell signaling activities versus its anticoagulant activity.  Signaling selective APC mutants were as potent as wt-APC in reducing endotoxin-induced mortality and providing neuroprotection; studies implied that APC molecular species with potent antithrombotic activity but without robust cytoprotective activity are not sufficient to reduce mortality in endotoxemia.  In summary, protein engineering can provide APC mutants that permit definitive in vivo mechanism of action studies for APC multiple activities, and such engineering may provide safer and more effective second generation APC mutants with reduced bleeding risk…. J.H.G.”