The research of Patrick D. Lyden, MD, focuses on translational stroke research. One theme involves understanding the role of thrombin in mediating cytotoxicity during ischemia. In collaboration with Roger Tsien at University of California, San Diego and other colleagues, Lyden's research has shown that during a stroke, thrombin enters the brain, adheres to neurons, and kills them via the protease activated receptor (PAR-1). His research has also shown that thrombin inhibitors block this cytotoxicity and ameliorate the behavioral and histological effects of stroke. Recently, Lyden and his colleagues have shown that thrombin inhibitor Argatroban powerfully protects the brain when delayed as late as three hours after stroke. Future studies are aimed at understanding the mechanism by which thrombin enters brain and whether thrombin plays any other roles, such as pre-conditioning. A second theme involves treating stroke with hypothermia. Lyden and his colleagues propose to address critical questions about cooling target-depth, duration, and delay-time window, as well as develop new tools for translational studies in this field. He aims to determine the relationship among target-depth, duration, and delay, and to develop new models for conducting further research into therapeutic hypothermia, considered the most potent putative neuroprotectant available.