The racial disparity in platelet PAR4 signaling enhances thrombus formation

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Black individuals have a higher mortality rate from coronary heart disease (CHD) than white individuals, even after adjusting for clinical and demographic confounders. Heightened platelet reactivity is associated with an increased risk for occlusive platelet-rich clot formation, the major cause of CHD-related mortality. Platelets from blacks were hyperactive compared to platelets from whites in response to protease activated receptor 4 (PAR4) stimulation even in the presence of dual antiplatelet therapy (DAPT), aspirin, and a P2Y12 receptor antagonist. However, it remains unknown whether the racial difference in PAR4-mediated platelet activation results in an increase in clot formation in blacks compared to whites. The long-term objective of this study is to better understand the underlying cause of the disparity in PAR4-mediated platelet reactivity and determine whether the difference in PAR4 activation leads to increased thrombosis in blacks relative to whites. To this end, Aim 1 will focus on delineating the mechanism responsible for the racial difference in PAR4 signaling. The candidate will acquire technical expertise in order to study how a polymorphism in PAR4, more common in blacks than whites, regulates PAR4 activation (K99 phase of Aim 1). The R00 phase of Aim 1 will determine whether differences in PAR4 activation enhance downstream signaling, and how rare PAR4 polymorphisms influence PAR4 activation. Further, it remains unknown if the racial disparity in PAR4-mediated platelet reactivity persists in platelets from cardiac patients on DAPT. Hence, in the K99 phase of Aim 2, patients on DAPT will be recruited and their platelet reactivity will be assessed to determine if the racial difference in PAR4-mediated platelet activation persists in individuals on DAPT. The R00 phase of Aim 2 will utilize a biorepository generated during the K99 phase to determine whether blacks have an increase in basal platelet activation compared to whites. To determine whether thrombosis differs between blacks and whites thrombus formation will be evaluated in vivo with humanized mouse (K99 phase of Aim 3), as well as ex vivo models (R00 phase; Aim 3). Additionally, humanized mouse models will be used to determine whether there is a racial difference in hemostasis (R00 phase of Aim 3). A better understanding of the mechanism responsible for the racial disparity in PAR4 signaling will provide evidence for targeted therapy to treat individuals with an increase in PAR4- mediated platelet reactivity. Additionally, as PAR1 antagonists are currently approved and PAR4 antagonists are in pre-clinical development, this work has important clinical implication as to which patients may benefit the most from selective PAR inhibition. This proposal describes an intensive training plan of didactic courses, seminars, and hands-on training that will differentiate the candidate from his mentor and allow him to develop an independent career in platelet disparities research.