School of Medicine W305C
10900 Euclid Ave
Cleveland, OH 44106-4965
The underlying theme of my research program is that protease activated receptor subtypes interact with one another to mediate the full range of thrombin signaling for activation of platelets, endothelial cells and mononuclear cells. Thrombin is the terminal enzyme in the clotting cascade that activates cells by cleaving the N-terminus of its receptors, protease activated receptors (PARs). PARs are G-proetin coupled receptors that signal through multiple G-proteins. Human platelets express 2 PAR subtypes, PAR1 and PAR4. PAR1 activation on platelets is rapid and requires low thrombin concentrations. Although PAR4 requires higher thrombin concentrations for activation, PAR4 is required for stable clot formation. PAR1 and PAR4 interact on the platelet surface and PAR1 lowers the amount of thrombin required for PAR4 activation by serving as a cofactor. Since thrombin is a potent platelet agonist, PAR1 and PAR4 are potential targets for anti-platelet therapies for patients that do not respond to current anti-platelet agents. In other tissues and cell types, PAR1 is co-expressed with PAR2. PAR2 is not directly activated by thrombin, but can be activated by thrombin-cleaved PAR1 via a transactivation mechanism. In sum, PAR1 cooperates with PAR2 or PAR4 on a variety of tissues to mediate full activation of these cells by thrombin. Therefore, studies examining thrombin signaling must take into account contributions of other PARs expressed on the cells of interest. In my lab we use a combination of enzyme kinetics, resonance energy transfer, cell based assays with cell lines and freshly isolated human and mouse platelets as well as animal models to examine the influence of the interaction of PAR subtypes on thrombin signaling.
The central hypothesis for the primary project of my lab is that PAR1 influences PAR4's interaction with thrombin, modulating the efficiency of PAR4 activation and signaling. The objective of this project is to determine how PAR1 and PAR4 interact to mediate thrombin signaling in platelets. Specifically, the project aims to identify the PAR1-PAR4 interaction interface and determine how the anionic region on the PAR4 exodomain contributes to platelet activation in vivo in the presence of PAR1. The long-term goal is to identify potential targets for anti-platelet therapies that do not pose a risk for bleeding by understanding how PAR1 and PAR4 interact with one another to mediate thrombin signaling for platelet activation.
Current lab members:
- Caileigh McKenna : 2011
- Daniel N. Noble: 2009-2010
- Sheetal Verma: 2010
Graduate students and postdoctoral scholars are welcome to join our lab to work on biophysical properties of Protease Activated Receptors (PARs) or the role of these receptors in platelet physiology and hemostasis.
Interested candidates please send CV, brief statement of research interests, and list of references to Marvin Nieman (email@example.com).
Current Case Western Reserve University graduate students are encouraged to contact Marvin Nieman (firstname.lastname@example.org) to discuss potential rotation projects in the laboratory.
Prospective graduate students please apply directly to the Molecular Therapeutic Training Program or the Biomedical Sciences Training Program at Case Western Reserve University. When you are accepted to either program spend one of your rotations working in our lab.
Our lab is located in the School of Medicine W305C at Case Western Reserve University.
School of Medicine W305C , 10900 Euclid Ave, Cleveland OH 44106-4965