Molecular Mechanisms of Platelet Granule Secretion
In order to perform their role in hemostasis and thrombosis, platelets must secrete their granule contents. We study the SNARE and SNARE accessory proteins required for normal granule release. We are also interested in the role the actin cytoskeleton serves in mediating platelet granule release and in how membrane remodeling occurs during platelet shape change and megakaryopoiesis. In addition, we use a variety of genetically modified mice to assess the role of platelet granule secretion in thrombus formation and in other disease models.
Thrombus formation is decreased in mice lacking platelet dense granules (right) compared to wild-type (left).
Chemical Genetic Analysis of Platelet Activation
We have performed forward chemical genetic analyses of protease-activated receptor 1 (PAR1)- mediated platelet granule release. In collaboration with the Broad Institute, we have screened hundreds of thousands of compounds and discovered several previously unidentified inhibitors of platelet activation. Among the compounds identified using this approach are several GPCR modulators that act via an allosteric mechanism. Ongoing research is directed at determining the mechanism of these novel molecular probes.
High throughput screening of platelet dense granule secretion.
Formation of Platelet Microparticles
Platelet microparticles are the most abundant microparticle subclass in the circulation. These microparticles are readily formed in vitro upon exposure of platelets to pharmacologic doses of agonists. Yet the mechanisms by which they are generated in vivo remain largely unknown. In an ongoing collaboration with the Italiano group, we have demonstrated that megakaryocytes produce microparticles. We have demonstrated that megakaryocyte-derived microparticles
circulate in the bloodstream and form the majority of "platelet-derived" microparticles in healthy individuals. Ongoing studies are directed at determining how megakaryocyte-derived micro- particles are formed and what function they serve in hemostasis and maintenance of vascular integrity.
The Flaumenhaft laboratory has been supported by generous funding from the following organizations:
NIH (NHLBI, NIDA)
American Heart Association
Howard Hughes Medical Institute
Burroughs Wellcome Foundation
American Society of Hematology
Charitable Leadership Foundation
Bayer Biological Products