Platelet Reprogramming During Inflammation

炎症期间的血小板重编程

基本信息

批准号：
10292889
负责人：
Matthew Thomas Rondina
金额：
--
依托单位：
VA SALT LAKE CITY HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10292889
关键词：
Ablation Affect Agonist Blood Platelets Blood coagulation Cell Nucleus Cell physiology Cells Cessation of life Chronic Clathrin Clinical Research Complication Data Disease Dissection Endocytosis Event Experimental Models Fibrinogen Functional disorder Gene Expression Gene Expression Regulation Genetic Genetic Transcription Hemostatic Agents Hospitals Human Immune Immune response In Vitro Infection Infectious Agent Inflammation Inflammatory Inherited Integral Membrane Protein Integrins Interferons Invaded Link Mediating Megakaryocytes Modeling Molecular Morbidity - disease rate Mus Organ failure Parents Pathway interactions Pharmacology Platelet aggregation Process Proteins Proteome Regulation Sepsis Syndrome TNF gene Testing Thrombosis Time Toxin Translations Veterans Work adverse outcome base cecal ligation puncture clinically relevant comorbidity genetic manipulation in vivo innovation military veteran mortality mouse model pathogen platelet function prevent prospective response septic septic patients stressor systemic inflammatory response thrombotic thrombotic complications transcriptome

Ablation Affect Agonist Blood Platelets Blood coagulation Cell Nucleus Cell physiology Cells Cessation of life Chronic Clathrin Clinical Research Complication Data Disease Dissection Endocytosis Event Experimental Models Fibrinogen Functional disorder Gene Expression Gene Expression Regulation Genetic Genetic Transcription Hemostatic Agents Hospitals Human Immune Immune response In Vitro Infection Infectious Agent Inflammation Inflammatory Inherited Integral Membrane Protein Integrins Interferons Invaded Link Mediating Megakaryocytes Modeling Molecular Morbidity - disease rate Mus Organ failure Parents Pathway interactions Pharmacology Platelet aggregation Process Proteins Proteome Regulation Sepsis Syndrome TNF gene Testing Thrombosis Time Toxin Translations Veterans Work adverse outcome base cecal ligation puncture clinically relevant comorbidity genetic manipulation in vivo innovation military veteran mortality mouse model pathogen platelet function prevent prospective response septic septic patients stressor systemic inflammatory response thrombotic thrombotic complications transcriptome

展开

项目摘要

Inflammation and sepsis is characterized by dysregulated host responses that span hemostatic, inflammatory, and immune continuums. Thrombosis is a common complication of sepsis, contributing to adverse outcomes including organ failure and death. The significance of this devastating dysregulated host response is demonstrated by data suggesting half of all hospital deaths, including the Veterans population, may be attributed to sepsis. Emerging evidence supports the concept that dysregulated platelet responses mediate the pathophysiology during inflammation. Nevertheless, the molecular mechanisms and functional consequences of dysregulated platelet functions during sepsis remain incompletely understood. Our proposal, entitled “Platelet Reprograming During Inflammation” will identify new pathways by which inflammatory agonists including, interferons (IFNs) regulate gene expression in platelets and their parent cell, the megakaryocyte (MK). Our preliminary studies have identified that the expression of interferon-induced transmembrane protein 3 (IFITM3) is robustly induced in human platelets during sepsis. Moreover, our data demonstrate that IFITM3 upregulates fibrinogen endocytosis in MKs and platelets, leading to platelet hyperreactivity and thrombosis. The regulation and function IFITM3 in MKs and platelets, or for that matter any other human cell, has never previously been identified. In this proposal, we will leverage prospective clinical studies in sepsis with in vitro and in vivo murine models. These complementary human and murine studies will allow us to demonstrate clinical relevance while also dissecting the mechanisms by which IFITM3 governs MK and platelet function during inflammation. These studies are translational and innovative as IFITM3 regulation of endocytosis, a process critical for cellular function. This has not previously been studied in MKs, platelets, or – for that matter - primary human cells. They will also determine for the first time whether inflammatory agonists regulate transcriptional and translational events in MKs and developing platelets. This work will test an important functional hypothesis and clarify pathophysiologic mechanisms of thrombosis during inflammation and sepsis. This proposal has both immediate translational potential for the thousands of Veterans estimated to develop sepsis, and will underlie additional progress for inflammatory diseases more broadly affecting the Veteran population.

炎症和败血症的特征是肿瘤，炎症，宿主反应失调，和免疫连续体。血栓形成是败血症的常见并发症，导致不良结果包括器官故障和死亡。这种毁灭性失调的宿主反应的重要性是通过数据表明，所有医院死亡的一半，包括退伍军人人口的一半都可以归因于败血症。新兴证据支持了血小板反应失调的概念介导炎症期间的病理生理。然而，分子机制和功能后果败血症期间血小板功能失调仍然不完全理解。我们的建议，名为“血小板在炎症期间重新编程”将确定炎症激动剂在内的新途径干扰素（IFNS）调节血小板及其母细胞中的基因表达，巨核细胞（MK）。我们的初步研究表明，干扰素诱导的跨膜蛋白3的表达（IFITM3）在败血症期间，在人血小板中诱导了强烈的诱导。此外，我们的数据表明IFITM3上调 MK和血小板中的纤维蛋白原内吞作用，导致血小板过度反应性和血栓形成。法规在MK和血小板中的功能IFITM3，或为此，任何其他人类细胞都从未有过确定。在此提案中，我们将利用体外和体内鼠类败血症的前瞻性临床研究型号。这些完整的人类和鼠研究将使我们能够证明临床相关性还剖析IFITM3在炎症过程中控制MK和血小板功能的机制。这些研究被翻译成创新为内吞作用的IFITM3调节，这是一个至关重要的过程细胞功能。以前尚未在MK，血小板或为此中研究这一点 - 主要人类细胞。他们还将首次确定炎症激动剂是否调节转录并在MK中翻译事件并开发血小板。这项工作将测试重要的功能假设和阐明注射和败血症期间血栓形成的病理生理机制。该提议对数千名退伍军人估计具有直接的翻译潜力发展败血症，并将为更广泛影响炎症性疾病的进一步进展。退伍军人人口。