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| Ashrafi, Kaveh |
| Barber, Diane L |
| Bernstein, Harold S. |
| Black, Brian L |
| Blanc, Paul D |
| Boushey, Homer A |
| Broaddus, V Courtney |
| Brown, James K |
| Caughey, George H |
| Chapman, Harold A |
| Charo, Israel F |
| Chatterjee, Kanu |
| Chuang, Pao-Tien |
| Clyman, Ronald I |
| Conklin, Bruce R |
| Coughlin, Shaun R |
| Derynck, Rik M |
| Dobbs, Leland G |
| Eisner, Mark D |
| Engel, Joanne N |
| Erle, David J |
| Fahy, John Vincent |
| Farese, Robert V |
| Fielding, Christopher J |
| Fielding, Phoebe |
| Fineman, Jeffrey R |
| Glantz, Stanton A |
| Grossman, William |
| Hawgood, Samuel |
| Ingraham, Holly A |
| Jan, Lily Y |
| Kan, Yuet W |
| Kane, John P |
| Kornberg, Thomas B |
| Kurtz, Theodore W |
| Kwok, Pui-Yan |
| Lazarus, Stephen C |
| Malloy, Mary J. |
| Martin, Gail R |
| Matthay, Michael A |
| Mcdonald, Donald M |
| Mikawa, Takashi |
| Minor, Daniel L |
| Mostov, Keith E |
| Nadel, Jay A |
| Ordahl, Charles P |
| Pitas, Robert E |
| Reiter, Jeremy F. |
| Rosen, Steven D |
| Shaw, Robin M. |
| Sheppard, Dean |
| Simpson, Paul C |
| Stainier, Didier Y. R. |
| Wang, Rong |
| Weiner, Orion D |
| Weisgraber, Karl H |
| Weiss, Arthur |
| Weiss, Ethan J |
| Werb, Zena |
| Wiener-Kronish, Jeanine |
| Young, William L |
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CVRI Scientists
Shaun R. Coughlin, M.D., Ph.D.
Professor of Medicine and Cellular & Molecular Pharmacology; Distinguished Professorship in Cardiovascular Biology & Medicine; CVRI Director
Research Interests:
Signaling mechanisms in cardiovascular biology and disease, thrombin signaling
Summary:
How are the thrombi that cause most heart attacks and strokes formed? How is normal blood clotting at a site of tissue injury triggered? Tissue injury initiates the formation of a protease called thrombin at the injury site, and thrombin is the central mediator of blood clotting. Proteases are best known for their ability to cleave or digest other proteins, but some can act like a hormone to trigger specific cellular responses. Indeed, thrombin causes platelets, small specialized blood cells, to aggregate at sites of injury to plug bleeding blood vessels. It is this same process that blocks diseased blood vessels in the heart or brain to cause heart attacks and some strokes. How does a protease like thrombin behave like a hormone to regulate the behavior of platelets and other cells? We've characterized a family of protease-activated receptors (PARs) that provide an answer. PAR1 is the key mediator of thrombin's effect on human platelets. Part of PAR1 is displayed on the outside of the platelet, poised to sense its environment. Thrombin binds to and cleaves this part of PAR1, and this cleavage event triggers a change in the shape of the receptor that sends information across the cell membrane to switch on signaling molecules inside the platelet. PAR1 is the prototype for a family of four related receptors that appear to account for most cellular responses to thrombin and related proteases. Our laboratory currently focuses on understanding the roles of protease and PAR signaling and, more broadly, G protein-coupled receptors in cardiovascular biology.
One important line of research uses mice made to lack one or more PARs. Such studies showed that PARs are necessary for platelets to respond to thrombin and for enlargement and propagation of platelet thrombi at sites of blood vessel injury. Interestingly, PAR signaling is unnecessary for formation of initial small juxtamural platelet thrombi, the kind of thrombin that are capable of plugging a small hole in the wall of a small blood vessel but not capable of blocking a major artery. Thus different signaling mechanisms appear to be important at different points in the development of a thrombus and exploiting such differences may permit the development of safer antithrombotic drugs. Specifically, PAR1 blockers may be useful in this regard. Mouse studies have also revealed that proteases and PARs play unexpected roles in the formation of the cardiovascular system and the nervous system in the embryo, roles which we are working to characterize.
Lastly, PARs are members of a much larger family of receptors known as G protein-coupled receptors. These receptors regulate a host of physiological processes and it is clear important roles remain to be uncovered. The ~350 G protein-coupled receptors in mice and humans couple through four main G protein families, Gs, Gq, Gi, and G12/13. We are ablating G12/13 and Gi signaling in specific cell types in mice to probe the roles of these pathways in cardiovascular development, metabolism, blood and bone formation, and other important processes, then using a candidate approach to identify the receptors and ligands involved. We expect these studies will point up new strategies for treating diseases of the systems under study.
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