Tilbake til søkeresultatene

FRIMED2-FRIPRO forskerprosjekt, medisin og helse

Development of novel therapeutic and diagnostic strategies in ischemic stroke based on Factor VII activating protease (FSAP).

Alternativ tittel: Oppdagelse av nye signalveier i hjerneslag på Faktor Syv Aktiverende Protease(FSAP).

Tildelt: kr 9,0 mill.

Blir vi skadet, blør vi til blodet tykner og danner en blodpropp. Hva ville skje hvis blodet ikke ville koagulere? Da ville alt blodet i kroppen lekket ut, og vi ville dø. På den annen side, hvis vi hadde for mye blodpropp, ville blod lett koagulere inne i kroppen etter den minste skaden. Slike blodpropper kan blokkere blodkar som forsyner hjertet eller hjernen, noe som kan føre til skade på organene. I hjernen kalles den resulterende døden av hjerneceller et hjerneslag. De fleste slag kan behandles ved raskt å tynne ut blodet med et enzym kalt tPA. Vi har oppdaget et nytt enzym, kalt FSAP, som kan brukes til å behandle hjerneslag. FSAP tynner ikke bare ut blodet, men det ser ut til å beskytte hjernecellene mot død. Vi vet ikke helt hvordan dette enzymet ser ut og hvordan det fungerer. Hvis vi kunne se enzymet og forstå hva det gjør, kan vi utvikle nye medisiner for å kurere mennesker med hjerneslag. Dette er målet med prosjektet vårt.

Academic impact: The publications arising from this project have addressed important questions that have led to a significant advancement of knowledge in this area of research. A total of 11 articles have been published and 5 are under preparation. Clinical impact: The preparation of recombinant FSAP and demonstration of its efficacy in two mouse models of stroke has been the most significant result of this project. These represent a realistic step towards improving the treatment for ischemic stroke patients. Economic impact: Analysis of the patentability of the current finding uncovered one patent application, US 2004/0063187 A1 which anticipated the therapeutic use of plasma FSAP and its combination with tPA for the treatment of stroke. Thus, we were not able to patent these findings.

Over 15 million strokes occur every year world-wide, a third of which result in death and another third in severe disability. Nearly 90% of all strokes are due to a clot in the brain which stops blood flow and rapidly kills brain tissue. We have discovered that an endogenous circulating protease, called Factor Seven Activating Protease (FSAP), can play an important role in the pathogenesis of stroke. About 5% of Europeans are carries of a polymorphism, Marburg I, that leads to a change in the sequence of FSAP resulting in low proteolytic activity. These carriers are more susceptible to stroke. Our studies with mouse models of stroke further demonstrate that endogenous FSAP is a protective factor in stroke. Based on these facts we hypothesize that FSAP could be useful in the therapy and diagnosis of stroke. To realize this potential we need to generate detailed knowledge about the mechanisms involved. One fundamental question is why is the Marburg I variant a risk factor for stroke? Is it because of lower proteolytic activity or does it cleave other substrates? Using a combination of recombinant protein expression, structure determination and phage display we will answer these questions. We will induce stroke in mice that have been manipulated to express the Marburg I variant of FSAP and compare this to wild type mice. This will help to explain why Marburg I carriers are more susceptible to stroke. We will elucidate detailed molecular mechanisms of the actions of FSAP on neurovascular cells. Furthermore, we will test whether measurement of FSAP in plasma can predict the outcome of stroke as well as predict the efficacy of treatment. On the basis of this knowledge we will test the efficacy of FSAP exogenous FSAP in stroke in vivo. This project will provide a detailed understanding of the biology of FSAP, leading to proof-of-concept studies demonstrating that FSAP is a valid therapeutic entity.

Publikasjoner hentet fra Cristin

Ingen publikasjoner funnet

Ingen publikasjoner funnet

Ingen publikasjoner funnet

Budsjettformål:

FRIMED2-FRIPRO forskerprosjekt, medisin og helse

Finansieringskilder