Project 3 - Abstract Three interrelated but independent hypotheses are being tested in this project. A.) Aptamers can serve as molecular probes to identify and study functionally important exosites on coagulation factor cofactors FVa and FVIIIa; B.) Aptamers targeting specific regions identified within FV and FVIII can serve as procoagulants by allosterically activating FV or preventing the binding of FVIII to vWF; and C.) Exosite binding Factor V and VIII aptamers will limit thrombosis in vivo and antidote oligonucleotides can be made to rapidly reverse the anticoagulant activity of such aptamers to restore normal hemostasis in animals.
Our specific aims are:
Aim 1 : To generate anticoagulant aptamers against coagulation factors Va and VIIIa and use them as novel probes for exosite interactions with the cofactors within the respective enzyme complexes.
Aim 2 : To generate novel procoagulant aptamers targeting the procofactor FV and FVIII Aim 3: To evaluate the ability of aptamers targeting exosites on Factor V/Va and VIII/VIIIa to act as potent yet safe antithrombotic agents.
Project 3 - Narrative The long-term objective of this project is to develop a more thorough understanding of coagulation enzymology to allow for the development of more effect therapeutic strategies to maintain health and limit the pathological consequences of inappropriate blood coagulation which remains one of the leading causes of morbidity and morality in the United States. Moreover, these studies have the potential to yield safe and effective, rapid onset anticoagulants (ROAs) to improve clinical outcomes for the millions of Americans requiring such therapeutics each year.