CD37 as a Regulator of Platelet Patho(Physiological) Responses

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SUMMARY Eighty-five percent (85%) of cardiovascular disease deaths occur due to either myocardial infarction (MI) or stroke, platelet-driven events. While antiplatelet therapy for secondary CVD prevention is well-established, antiplatelet therapy is not commonly prescribed to prevent a first MI or stroke as the cardioprotective benefits are offset by major bleeding risk. The well-established role of platelets in the pathogenesis of MI and stroke and the lack of platelet-directed therapeutic options for primary CVD prevention necessitates investigating novel platelet targets which would impact the multifaceted effects of platelets without impacting hemostasis. Furthermore, while platelets were once considered primarily mediators of hemostasis and thrombosis, it is now understood that they play an important role as immune mediators. Platelets play central roles in the chronic inflammation that fuels atherosclerosis, from the initial innate immune response to damage-associated molecular pattern proteins to the engagement of adaptive immunity. To effectively target this axis, a better understanding of the pathways and cell-cell communication networks by which platelets promote atherogenesis and inhibit inflammation resolution in CVD Is required. By unbiased platelet sequencing, we have identified a novel regulator of platelet activation responses, CD37. This proposal aims to understand how CD37 regulates platelet functional responses and how targeting platelet CD37 may be a viable therapeutic approach to reduce (patho)physiological platelet responses. In Aim 1 we will establish the role of CD37 in platelet activation responses and identify protein-binding partners in CD37-enriched membrane microdomains. Aim 2 will assess if targeting platelet CD37 alters atherosclerosis and plaque stability. The studies will serve as an essential foundation to demonstrate the viability of targeting platelet CD37 to reduce thrombosis, atherogenesis, and systemic inflammation. If our hypotheses prove accurate, CD37, our newly identified platelet activity gene, could be targeted to prevent and treat a wide variety of platelet-mediated disorders, including cardiovascular disease.