Platelet Exocytosis and Endocytosis in Thrombosis and Immunity

摘要 令人惊讶的是，血小板能够与其微环境进行双向相互作用 通过基本的细胞过程，这些过程在很大程度上是未知的。在这份R35提案中，我们对 我们积极的研究主题：一是揭示胞吐作用在止血和 另一种是将内吞作用作为一种进入途径来确定血小板在先天性疾病中的作用。 豁免权。通过将这两个区域联系起来，我们可以更深入地了解血小板如何与 它们的微环境。尽管在理解血管损伤的信号方面取得了进展 检测，我们对激活的血小板如何执行凝块形成所需步骤的看法是 有限的。我们探讨了血小板分泌的机制及其如何影响止血， 使用基因改变的模型，并确定调节分泌控制血栓 在不影响止血的情况下增长。为了在这一进展的基础上，更好地理解 血小板胞吐显然是需要的，因此可以制定合理的治疗策略。我们的工作 关于血小板内吞、内溶酶体运输和内吞货物的处理导致 发现血小板携带病原体，如病毒，并被激活。越来越多的人， 血小板与免疫反应有关，但其背后的机制 非止血功能在很大程度上是未知的。人们对血小板内吞作用知之甚少 此外，对血小板如何运输和处理内吞物质几乎一无所知。我们的 R35研究计划寻求通过采取全面的方法来填补这些知识空白 研究血小板的“细胞生物学”。在我们过去创新工作(&gt；50种出版物)的基础上，我们将 进一步定义血小板膜运输(内吞作用、胞吐作用、货物分类/处理， 等)。我们假设双向转运过程，即胞内和胞吐作用是必不可少的。 用于血小板特异性功能，特别是血栓形成和先天免疫反应。致信地址 在这一假说中，我们将从机制和机制两个方面研究血小板的胞吐和内吞。 使用一套广泛的试剂、转基因小鼠品系和 技术。展望未来，我们将使用这些强大的工具和方法来定义 血小板膜转运(外吞和内吞)影响止血/血栓形成和 在分子和机体水平上的免疫反应。生成的数据直接 适用于对人类疾病，特别是血栓性疾病的认识和治疗 这占全世界四分之一的死亡和慢性病毒血症，例如艾滋病/艾滋病毒1，其中 增加心血管疾病的风险。

Abstract Surprisingly, platelets are capable of bidirectional interactions with their microenvironment through basic cellular processes that are largely unexplored. In this R35 proposal, we expand on our active research themes: one unraveling the mechanistic role of exocytosis in hemostasis and the other investigating endocytosis as an entry pathway to define the role of platelets in innate immunity. By linking these two areas, we can gain deeper insights into how platelet interact with their microenvironments. Despite advances in understanding signaling from vascular damage detection, our view of how activated platelets execute the steps needed for clot formation is limited. We have probed the mechanisms of platelet secretion and how it affects hemostasis, using genetically altered models, and determined that modulating secretion controls thrombus growth without compromising hemostasis. To build on that advance, a better understanding of platelet exocytosis is clearly needed so logical therapeutic strategies can be developed. Our work on platelet endocytosis, endo-lysosomal trafficking, and processing of endocytosed cargo led to the discovery that platelets take up pathogens, e.g., viruses, and are activated. Increasingly, platelets are being associated with immune responses, yet the mechanisms underlying these non-hemostatic functions are largely unknown. Very little is known about platelet endocytosis and next to nothing is known about how platelets traffic and process endocytosed material. Our R35 research program seeks to fill these gaps in knowledge by taking a holistic approach to the study of platelet “cell biology”. Building on our innovative past work (>50 publications), we will further define platelet membrane trafficking (endocytosis, exocytosis, cargo sorting/processing, etc.). We hypothesize that bidirectional trafficking processes, endo- and exocytosis, are essential for platelet-specific functions, specifically thrombosis and innate immune responses. To address this hypothesis, we will examine platelet exocytosis and endocytosis at mechanistic and physiological levels using an extensive suite of reagents, transgenic mouse strains, and technologies. Going forward, we will use these powerful tools and approaches to define how platelet membrane trafficking (both exo- and endocytosis) affects hemostasis/thrombosis and immune responses at molecular and organismal levels. The data generated are directly applicable to the understanding and treatment of human disease, especially thrombotic diseases which accounts for 1 in 4 deaths world-wide and chronic viremia, e.g., AIDS/HIV1, which increases CVD risk.