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Goal: Characterize the molecular mechanisms causing racial disparities in stroke mediated by protease activated receptor 4 (PAR4) hyperreactivity in African American compared to subjects European Americans.

We discovered that a common Ala120Thr functional variant in PAR4 causes the racial difference in PAR4-induced platelet aggregation (Nat Med 2013; Blood 2014). We genotyped >12,000 patients and demonstrated the Thr120 variant was associated with an increased ischemic stroke risk and a lower rate of GUSTO moderate/severe bleeding. We are using human platelets and megakaryocytes, and our novel humanized PAR4 mouse to investigate the molecular basis of the effects of the PAR4 Ala120Thr variant on PAR4 desensitization, Ischemia/Reperfusion injury and novel anti-PAR4 agents.