CD37 as a Regulator of Platelet Patho(Physiological) Responses

总结 百分之八十五（85%）的心血管疾病死亡是由于心肌梗死（MI）或 中风血小板驱动的事件虽然抗血小板治疗用于二级CVD预防是公认的， 抗血小板治疗通常不用于预防首次MI或卒中，因为心脏保护益处 会被大出血风险抵消血小板在心肌梗死和卒中发病机制中的作用已得到公认， 缺乏血小板导向的治疗选择，需要研究新的 血小板靶点，其将影响血小板的多方面作用而不影响止血。 此外，虽然血小板曾经被认为是止血和血栓形成的主要介质，但现在 了解到它们作为免疫介质发挥着重要作用。血小板在慢性炎症中起着核心作用， 从最初的先天免疫反应到损伤相关分子， 模式蛋白参与获得性免疫。为了有效地瞄准这一轴心， 血小板促进动脉粥样硬化形成和抑制动脉粥样硬化形成的途径和细胞间通讯网络 需要CVD中的炎症消退。 通过无偏血小板测序，我们已经确定了一种新的血小板活化反应调节剂，CD37。 该提案旨在了解CD37如何调节血小板功能反应以及如何靶向血小板 CD37可能是一种可行的治疗方法，以减少（病理性）生理血小板反应。 在目标1中，我们将确定CD37在血小板活化反应中的作用，并确定蛋白结合伴侣 在富含CD37的膜微区中。目标2将评估靶向血小板CD37是否改变动脉粥样硬化 和斑块稳定性。这些研究将成为证明目标选择可行性的重要基础 血小板CD37，以减少血栓形成，动脉粥样硬化和全身炎症。如果我们的假设证明 准确地说，CD37，我们新发现的血小板活性基因，可以有针对性地预防和治疗各种各样的 血小板介导的疾病，包括心血管疾病。

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.