Platelet Endocytosis in Innate Immunity

先天免疫中的血小板内吞作用

• 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
• 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

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，