Platelet Endocytosis in Innate Immunity

令人惊讶的是，血小板能够进行许多细胞过程（即，RNA剪接，翻译， 糖基化、内吞作用）;然而，它们对血小板功能的影响常常不清楚。作为 循环哨兵，血小板通过内吞作用对脉管系统取样。一些 内吞货物（即，纤维蛋白原）运输到颗粒;然而，其他材料引发 血小板反应在这个建议中，我们表明病原体内吞作用诱导免疫- 激活血小板。这可能会导致心血管风险增加， 持续感染（如HIV-1/艾滋病患者）。在这个应用程序中，我们建立在 我们的新发现，假设血小板内吞作用对先天免疫至关重要， 对病毒感染的反应。为了验证这一假设，我们重点研究血小板内吞作用 在模拟慢性炎症的动物模型中促进基于Toll样受体（TLR）的信号传导 HIV-1/艾滋病。使用新的基因改变的小鼠（Arf 6-/-、VAMP-3-/-和Syntaxin-2/4-/-）， 在不同的内吞步骤有缺陷，我们将讨论作用，途径， 血小板内吞机制，特别关注血小板如何与HIV-1相互作用 病毒我们提出两个具体目标：目标1。确定缺陷血小板的影响 在病毒血症模型中，内吞作用对先天免疫应答的影响。目标2.确定 血小板内吞系统的机制和途径。我们的建议促进血小板 作为脉管系统的主动监测器，持续地与它们相互作用并解释它们， 环境，同时循环。在这种情况下，血小板利用内吞作用连续地 采样它们的微环境，并通过内吞运输，处理和评估线索 引发对血小板内吞的反应。我们的工作将使我们深入了解 血小板功能在全身感染，从而重塑使用抗血栓 治疗最后，了解血小板内吞作用将揭示新的策略， 用可用于治疗CVD的治疗剂装载血小板的效率。

Surprisingly, platelets are capable of many cellular processes (i.e., RNA splicing, translation, glycosylation, endocytosis); however, their effects on platelet function are often unclear. As circulating sentries, platelets sample the vasculature via endocytosis. Some of the endocytosed cargo (i.e., fibrinogen) traffics to granules; however, other material initiates platelet responses. In this proposal, we show that pathogen endocytosis induces immuno- activation of platelets. This likely contributes to the increased cardiovascular risks associated with persistent infections, (as seen in HIV-1/AIDS patients). In this application, we build on our novel findings, hypothesizing that platelet endocytosis is critical for innate immune response to viral infections. To test this hypothesis, we focus on how platelet endocytosis facilitates Toll-like Receptor (TLR)-based signaling in an animal model that mimics chronic HIV-1/AIDS. Using novel, genetically-altered mice (Arf6-/-, VAMP-3-/-, and Syntaxin-2/4-/-), which are defective at different endocytic steps, we will address the roles, routes, and mechanisms of platelet endocytosis, with specific focus on how platelets interact with HIV-1 virus. We propose two specific aims: Aim 1. Determine the effects of defective platelet endocytosis on innate immune responses in a model of viremia. Aim 2. Determine the mechanisms and routes of the platelet endocytosis system. Our proposal advances platelets as active monitors of the vasculature, continuously interacting with and interpreting their environment while circulating. In this scenario, platelets use endocytosis to continuously sample their microenvironment and, through endocytic trafficking, process and evaluate cues that initiate responses to what the platelets have endocytosed. Our work will yield insights into platelet function during systemic infections, thus reshaping the uses of anti-thrombotic therapies. Finally, understanding platelet endocytosis will uncover novel strategies to increase the efficiency of loading platelets with therapeutics that can be used to treat CVD.