The protective role of endogenous FSAP in 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 endogenous FSAP is protective in mouse stroke models.
Details:
92 mice will be used in the project. In this application we have planned studies using of FSAP-/- knockout mice as well as FSAPH360F mice to determine the role of FSAP in stroke. FSAPH360F mice have a point mutation in the FSAP gene that inactivates the protease domain akin to the MI polymorphism in humans. Thus comparing the FSAP-/- mice with the FSAPH360F mice will show us whether the effect of FSAP is mediated via the proteolytic activity or not. Different possibilities exist for modeling stroke in mice and these models emphasize different aspects of stroke. By using two different models of stroke we hope to obtain robust results that will provide a solid basis for any conclusions reached. 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.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. 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.
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 endogenous FSAP is protective in mouse stroke models.
Details:
92 mice will be used in the project. In this application we have planned studies using of FSAP-/- knockout mice as well as FSAPH360F mice to determine the role of FSAP in stroke. FSAPH360F mice have a point mutation in the FSAP gene that inactivates the protease domain akin to the MI polymorphism in humans. Thus comparing the FSAP-/- mice with the FSAPH360F mice will show us whether the effect of FSAP is mediated via the proteolytic activity or not. Different possibilities exist for modeling stroke in mice and these models emphasize different aspects of stroke. By using two different models of stroke we hope to obtain robust results that will provide a solid basis for any conclusions reached. 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.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. 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.