Marvin Nieman, Ph.D.
The activation of P2Y12, PAR1 and PAR4 are key events in platelet activation, which are regulated by homo- and hetero-oligomers (top panel). In the presence of clopidogrel and vorapaxar, PAR4 becomes a primary signaling receptor on the platelet surface (lower panel). Inter-individual variability in PAR4 reactivity has the potential to be a determining factor of overall platelet activation for patients on a P2Y12 antagonist and vorapaxar. (from Arterioscl. Thromb. Vasc. Biol. 2014;34:2524-36.)
School of Medicine W305C
10900 Euclid Ave
Cleveland, OH 44106-4965
Hemostasis is the response to an injury to prevent blood loss from a damaged vessel. At the site of injury circulating platelets respond to agonists such as thrombin, collagen, ADP, and thromboxane to become adhesive and form a thrombus. In cardiovascular disease, platelets can become activated and cause a thrombus within the vessel causing a heart attack or stroke. Therefore, anti-platelet therapy is a central component for managing cardiovascular disease. However, little is known about how receptors on the platelet surface interact with each other to modulate their function. Our basic science research seeks to provide the fundamental understanding of how these therapeutic targets function at the molecular level. For example, heterotypic receptor complexes may initiate discrete signaling events from individual receptors. These receptor complexes may provide therapeutic targets that have not been recognized or dictate how patients respond to current therapies.
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 and endothelial cells. Thrombin is a potent platelet agonist that signals through PAR1 and PAR4 to mediate adhesion and aggregation. PAR4 is associated with a prolonged stimulus as measured by intracellular Ca2+-mobilization and may be required for stable clot formation. The rate of PAR4 activation by thrombin is enhanced ~10 fold due to a thrombin-dependent association with PAR1. Heterodimerization may be a common theme for regulating signaling because three major platelet GPCRs (PAR1, PAR4, P2Y12) have agonist depending interactions. PAR4 is at the center of this group of receptors since it interacts with both PAR1 and P2Y12. Moreover, PAR1 and P2Y12 are the targets of vorapaxar and clopidogrel, respectively, which makes PAR4 the primary receptor for patients on these therapies. The increased reliance on PAR4 in this setting may have particular importance given the recent observation that there are race differences in PAR4 reactivity.
- Nieman MT. PARtitioning protease signaling. Blood. 2015;125:1853-5
- Mumaw MM, de la Fuente M, Arachiche A, Wahl III JK, Nieman MT. Development and characterization of monoclonal antibodies against protease activated receptor 4 (PAR4). Thromb Res. 2015;135:1165-71.
- Mumaw M and Nieman MT. Race differences in platelet reactivity. Is PAR4 a predictor of response to therapy? Arterioscl. Thromb. Vasc. Biol. 2014;34:2524-36.
- Edelstein LC, Simon LM, Lindsay CR, Kong X, Montoya RT, Tourdot BE, Chen ES, Ma L, Coughlin S, Nieman M, Holinstat M, Shaw C, Bray PF. Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race. Blood. 2014; Epub ahead of print Oct 7.
- Mumaw M, de la Fuente M, Nobel DN, Nieman MT. Targeting the anionic region of human protease activated receptor 4 (PAR4) inhibits platelet aggregation and thrombosis without interfering with hemostasis. J Thromb Haemost. 2014;12:1331-41 PMCID: 4127092.
- Arachiche A, de la Fuente M, Nieman MT. Platelet specific promoters are insufficient to express Protease Activated Receptor 1 (PAR1) transgene in mouse platelets. PLoS One. 2014;9:e97724 PMCID 4022678.
- Arachiche A, Mumaw MM, de la Fuente M, Nieman MT. Protease-activated Receptor 1 (PAR1) and PAR4 Heterodimers Are Required for PAR1-enhanced Cleavage of PAR4 by alpha-Thrombin. J Biol Chem. 2013;288:32553-62. PMCID: 3820888.
- Arachiche A, de la Fuente M, Nieman MT. Calcium Mobilization And Protein Kinase C Activation Downstream Of Protease Activated Receptor 4 (PAR4) Is Negatively Regulated By PAR3 In Mouse Platelets. PLoS One. 2013;8:e55740. PMCID: 3566007.
- de la Fuente M, Noble DN, Verma S, Nieman MT. Mapping human protease-activated receptor 4 (PAR4) homodimer interface to transmembrane helix 4. J Biol Chem. 2012;287:10414-23. PMCID: 3322995.
- Nieman MT. Protease-activated receptor 4 uses anionic residues to interact with alpha-thrombin in the absence or presence of protease-activated receptor 1. Biochemistry. 2008;47:13279-86.
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 (firstname.lastname@example.org).
Current Case Western Reserve University graduate students are encouraged to contact Marvin Nieman (email@example.com) 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