Athan Kuliopulos

Assistant Professor of Medicine and Biochemistry

New England Medical Center and Tufts University School of Medicine

Phone:
Office: (617) 636-8482
Lab: (617) 636-8486
Fax: (617) 636-4833

Email: athan.kuliopulos@tufts.edu

MCRI's Hemostasis and Thrombosis Labratory

Research Focus - Signal Transduction of Peptide Receptors


Our research interests focus on a novel class of cell-surface protease-activated receptors (PARs). These receptors are widely
expressed throughout human tissues including vascular cells and platelets. Cleavage of the PARs can elicit many cellular responses such as platelet aggregation, inflammation, chemotaxis, mitogenesis, apoptosis, and angiogenesis. These receptors have also been implicated in the pathological processes leading to heart disease and cancer.


Ongoing Projects:

1. Thrombin Signaling in Platelets. This project studies the mechanism by which high (PAR1) and low affinity (PAR4) thrombin receptors are activated by thrombin using structural, biochemical and genetic approaches along with whole animal systems. The kinetics of intracellular signaling is measured by Ca2+ flux measurements, ATP-granule release, platelet-platelet aggregation and clot retraction. In collaboration with Dr. Jim Baleja, NMR structural studies of extracellular PAR domains and macromolecular interactions of the receptors with other soluble and cell-surface regulatory proteins are explored.

 

2. Molecular Interactions Between PARs and Intracellular Effectors. The molecular determinants of coupling between PARs and G proteins and other intracellular effectors are unknown. We have employed a yeast genetic system comprised of co-expressed PAR1 and mammalian G proteins and have identified a novel signal transference mechanism between the N-terminal alpha-helix of the Ga subunit and PAR1.

 

3. Effects of Fibrinolytic Therapy on Platelet/Endothelial Cell Function. Tissue plasminogen activator (t-PA) is a widely used and
effective agent for thrombolysis in patients suffering acute myocardial infarction. However, it is clear from several large clinical trials that the high levels of plasmin that are generated by t-PA can cause severe complications such as hemorrhage, neuronal injury, or even paradoxical activation of the hemostatic mechanism. To explain some of these untoward effects, we have demonstrated that plasmin can both activate and inactivate PAR receptors on platelets under ex vivo conditions and on platelets isolated from patients who have undergone thrombolytic therapy.

 

For more information see: Hemostasis and Thrombosis Laboratory Focus and Highlights


Recent Publications

  1. Andrabi, S. S., Azam, M., Kamath, L., Sahr, K. E., Kuliopulos, A., and Chishti, A. H. (2001). Disruption of the mouse mu-calpain gene reveals an essential role in platelet function. Mol Cell Biol 21, 2213-2220. PubMed Abstract
  2. Jacques, S. L., LeMasurier, M., Sheridan, P. J., Seeley, S. K., and Kuliopulos, A. (2000). Substrate-assisted catalysis of the PAR1 thrombin receptor. Enhancement of macromolecular association and cleavage. J Biol Chem 275, 40671-40678. PubMed Abstract
  3. Covic, L., Gresser, A. L., and Kuliopulos, A. (2000). Biphasic kinetics of activation and signaling for PAR1 and PAR4 thrombin receptors in platelets. Biochemistry 39, 5458-5467.
    PubMed Abstract
  4. Swift, S., Sheridan, P. J., Covic, L., and Kuliopulos, A. (2000). PAR1 thrombin receptor-G protein interactions. Separation of binding and coupling determinants in the galpha subunit. J Biol Chem 275, 2627-2635. PubMed Abstract
  5. Kuliopulos, A., Covic, L., Seeley, S. K., Sheridan, P. J., Helin, J., and Costello, C. E. (1999). Plasmin desensitization of the PAR1 thrombin receptor: kinetics, sites of truncation, and implications for thrombolytic therapy. Biochemistry 38, 4572-4585. PubMed Abstract

For more publications see: Hemostasis and Thrombosis Labratory Publications

Coworkers:

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