Platelet Exocytosis and Endocytosis in Thrombosis and Immunity

血栓形成和免疫中的血小板胞吐作用和内吞作用

• 批准号: 9894537
• 负责人: SIDNEY Waldo WHITEHEART
• 金额: $ 97.09万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9894537
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Area; Blood Platelets; Blood Vessels; Cell physiology; Cellular biology; Cessation of life; Chronic; Coagulation Process; Cytoplasmic Granules; Data; Detection; Endocytosis; Exocytosis; Growth; HIV-1; Hemostatic function; Immune response; Immune system; Immunity; Innate Immune Response; Knowledge; Link; Membrane; Modeling; Molecular; Mouse Strains; Natural Immunity; Pathway interactions; Physiological; Process; Publications; Reagent; Research; Risk; Role; Signal Transduction; Sorting - Cell Movement; Technology; Therapeutic; Thrombosis; Thrombus; Transgenic Mice; Viremia; Virus; Work; holistic approach; human disease; innovation; insight; pathogen; programs; tool; trafficking

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.

摘要 令人惊讶的是，血小板能够与其微环境双向相互作用 通过基本的细胞过程，这是很大程度上未被探索。在这个R35提案中，我们扩展了 我们积极的研究主题：一是阐明胞吐作用在止血中的机制作用， 另一个是研究内吞作用作为进入途径，以确定血小板在先天性巨噬细胞中的作用。 免疫力通过将这两个领域联系起来，我们可以更深入地了解血小板如何与 他们的微环境。尽管对血管损伤信号的理解取得了进展， 检测，我们对活化血小板如何执行凝块形成所需步骤的看法是 有限公司我们已经探索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 生长而不影响止血。在此基础上，更好地了解 显然需要血小板胞吐作用，因此可以开发合理的治疗策略。我们的工作 对血小板内吞作用、内溶体运输和内吞货物的加工的影响， 血小板吸收病原体的发现，例如，病毒，并被激活。越来越多的是， 血小板与免疫反应有关，但这些反应的机制 非止血功能在很大程度上是未知的。对血小板内吞作用知之甚少 几乎不知道血小板如何运输和处理内吞物质。我们 R35研究计划旨在通过采取全面的方法来填补这些知识空白， 研究血小板“细胞生物学”。基于我们过去的创新工作（超过50篇出版物），我们将 进一步定义血小板膜运输（内吞作用，胞吐作用，货物分选/加工， 等）。我们推测，双向运输过程，内分泌和胞吐，是必不可少的， 血小板特异性功能，特别是血栓形成和先天免疫反应。解决 基于这一假设，我们将从机制和机制上研究血小板的胞吐和胞吞作用， 使用广泛的试剂套件，转基因小鼠品系， 技术.展望未来，我们将使用这些强大的工具和方法来定义如何 血小板膜运输（胞吞和胞吞）影响止血/血栓形成， 分子和生物体水平的免疫反应。生成的数据直接 适用于理解和治疗人类疾病，特别是血栓性疾病， 占全球死亡人数的四分之一，以及慢性病毒血症，例如，艾滋病/艾滋病毒1， 增加CVD风险。