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Trial Lecture – time and place
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Adjudication committee
- First opponent: Professor Johann Brandstetter, Paris Lodron University Salzburg,
- Second opponent: Associate Professor Gerry Nicolaes, Maastricht University,
- Third member and chair of the evaluation committee: Associate professor Helene Knævelsrud, University of Oslo
Chair of the Defence
Associate Professor Jean-Luc Boulland, University of Oslo
Principal Supervisor
Professor Sandip Kanse, University of Oslo
Summary
A blood clot in brain vessels can cause a stroke, a major cause of death and disability. Previous research showed that Factor VII Activating Protease (FSAP), a blood protease, improved stroke outcome in mice by accelerating clot lysis and exhibiting neuroprotective effects. However, the molecular mechanisms underlying the actions of FSAP remain unclear. This thesis aims to bridge this gap by conducting a comprehensive biochemical analysis of FSAP and its interactions with substrates and inhibitors.
FSAP circulates as an inactive enzyme. It is activated by intracellular factors such as histones and heparin. The activation mechanism was elucidated using AlphaFold software to predict the 3D structure of FSAP, identifying potential activator binding sites in its heavy chain. Recombinant FSAP, its heavy and light chains were expressed in insect cells and the relevance of activator binding to heavy chain was confirmed experimentally. It was difficult to produce the light chain with a functional protease domain, therefore it was expressed in bacteria. Mutants of this domain were generated to map regions responsible for interactions with substrates (fibrinogen and histones) and inhibitors (C1-inhibitor and alpha2-antiplasmin). These findings provide a basis for improving the selectivity of FSAP towards its substrates and increasing its resistance to inhibitors, potentially improving its therapeutic efficacy.
The role of FSAP in hereditary angioedema (HAE), was also investigated. HAE leads to excessive swelling, especially in the respiratory tract, due to C1 inhibitor deficiency. C1 inhibitor deficiency also caused FSAP over activation in these patients, but this does not contribute to disease symptoms.
This study on the atomic-level function of FSAP and its interactions with its partners, coupled with generation of novel reagents, may lead to further advancements in stroke therapy.
Additional information
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