FSAP as therapy for ischemic stroke
Hypothesis:
FSAP (Factor VII-activating protease) is a plasma protease that is homologous to other proteins in the coagulation pathway. 5 % of all Europeans are carriers of a single nucleotide polymorphism (SNP) which is called the Marburg I (MI) polymorphism. Due to this SNP there is an alteration in the gene sequence that leads to inactivation of the protein. MI carriers are at an increased risk for getting stroke. Our previous studies have shown that FSAP-/- mice have more severe strokes than their WT counterparts. Thus, both in humans and mice, it appears that FSAP has a protective effect in stroke. In order to use FSAP for diagnostic and therapeutic purposes, further pre-clinical experiments are essential. In this application we will test the hypothesis that exogenously applied FSAP is protective in mouse stroke models. These experiments may lead to the development of new therapies in stroke.
Details:
144 male mice will be used in the project. Stroke will be induced in mice using two different procedures and the therapeutic efficacy of recombinant FSAP will be tested on infarct volume and functional outcome. In humans, stroke itself is not painful and this would be assumed to be the case in mice. Surgical procedure associated with stroke can lead to moderate pain in mice.These experiments will lead to the development of FSAP as a possible adjunct therapy for stroke that will potentially benefit a large number of patients. Replacement is not possible because of high complexity of this pathological condition. Reduction is achieved by appropriate planning of the experiments. The procedures used are already well established and refined as documented in a number of publications.
FSAP (Factor VII-activating protease) is a plasma protease that is homologous to other proteins in the coagulation pathway. 5 % of all Europeans are carriers of a single nucleotide polymorphism (SNP) which is called the Marburg I (MI) polymorphism. Due to this SNP there is an alteration in the gene sequence that leads to inactivation of the protein. MI carriers are at an increased risk for getting stroke. Our previous studies have shown that FSAP-/- mice have more severe strokes than their WT counterparts. Thus, both in humans and mice, it appears that FSAP has a protective effect in stroke. In order to use FSAP for diagnostic and therapeutic purposes, further pre-clinical experiments are essential. In this application we will test the hypothesis that exogenously applied FSAP is protective in mouse stroke models. These experiments may lead to the development of new therapies in stroke.
Details:
144 male mice will be used in the project. Stroke will be induced in mice using two different procedures and the therapeutic efficacy of recombinant FSAP will be tested on infarct volume and functional outcome. In humans, stroke itself is not painful and this would be assumed to be the case in mice. Surgical procedure associated with stroke can lead to moderate pain in mice.These experiments will lead to the development of FSAP as a possible adjunct therapy for stroke that will potentially benefit a large number of patients. Replacement is not possible because of high complexity of this pathological condition. Reduction is achieved by appropriate planning of the experiments. The procedures used are already well established and refined as documented in a number of publications.