Platelet Endocytosis in Innate Immunity

先天免疫中的血小板内吞作用

基本信息

批准号：
9362971
负责人：
SIDNEY Waldo WHITEHEART
金额：
$ 44.16万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9362971
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Address Affect Agonist Albumins Animal Model Area Binding Biogenesis Blood - brain barrier anatomy Blood Platelets Blood Tests Blood-Borne Pathogens Cardiovascular Diseases Cell physiology Cells Cellular biology Chronic Clot retraction Communicable Diseases Cues Cytoplasmic Granules DNA Data Dextrans Endocytosis Environment Fibrinogen Goals HIV-1 Hemorrhage Hemostatic function Image Immune Immune response Immune system Infection Injection of therapeutic agent Innate Immune Response Innate Immune System Integrins Kinetics Knockout Mice LAMP-1 Label Leukocytes MPL gene Maps Measurement Measures Mediating Modeling Molecular Monitor Mus Natural Immunity Pathway interactions Patients Pattern Pharmaceutical Preparations Phase Physiological Platelet Activation Positioning Attribute Preparation Process Proteins Public Health RNA Splicing Recycling Role Route Sampling Sepsis Signal Transduction Stream Surface Surveys System Systemic infection Testing Therapeutic Thrombocytopenia Thrombosis Thrombus Toll-like receptors Transgenic Mice Translations Viral Viremia Virion Virus Virus Diseases Work antiretroviral therapy base cardiovascular disorder risk cardiovascular risk factor detector disorder risk emergency service responder experimental study glycosylation in vivo Model insight novel novel strategies particle pathogen receptor response syntaxin-2 trafficking uptake

项目摘要

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.

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往往尚不清楚。作为作为循环哨兵，血小板通过内吞作用对脉管系统进行采样。一些内吞的货物（即纤维蛋白原）运输至颗粒；然而，其他材料会引发血小板反应。在这个提案中，我们表明病原体内吞作用诱导免疫血小板的活化。这可能会导致相关的心血管风险增加持续感染（如 HIV-1/艾滋病患者）。在此应用程序中，我们建立在我们的新发现假设血小板内吞作用对于先天免疫至关重要对病毒感染的反应。为了检验这个假设，我们重点关注血小板内吞作用如何在模拟慢性病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。使用新型基因改造小鼠（Arf6-/-、VAMP-3-/- 和 Syntaxin-2/4-/-），在不同的内吞步骤中存在缺陷，我们将讨论其作用、途径和血小板内吞作用机制，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病毒血症模型中的内吞作用对先天免疫反应的影响。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，不断地与它们互动并解释它们循环时的环境。在这种情况下，血小板利用内吞作用不断地对它们的微环境进行采样，并通过内吞运输、处理和评估线索启动对血小板内吞物质的反应。我们的工作将深入了解全身感染期间血小板的功能，从而重塑抗血栓药物的用途疗法。最后，了解血小板内吞作用将揭示增加血小板内吞作用的新策略用可用于治疗 CVD 的疗法装载血小板的效率。