Platelet Reprogramming During Inflammation

炎症和脓毒症的特点是宿主反应失调，包括止血、炎症、 和免疫连续体。血栓形成是脓毒症的常见并发症，会导致不良后果 包括器官衰竭和死亡。这种毁灭性的失调宿主反应的意义在于 数据表明，一半的医院死亡（包括退伍军人）可能归因于 败血症。新出现的证据支持血小板反应失调介导的概念 炎症期间的病理生理学。然而，分子机制和功能后果 脓毒症期间血小板功能失调仍不完全清楚。我们的提案题为“血小板 炎症期间的重编程”将确定炎症激动剂的新途径，包括： 干扰素 (IFN) 调节血小板及其母细胞巨核细胞 (MK) 中的基因表达。我们的 初步研究发现，干扰素诱导的跨膜蛋白3（IFITM3）的表达 在脓毒症期间在人类血小板中被强烈诱导。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，导致血小板高反应性和血栓形成。法规 IFITM3 在 MK 和血小板或任何其他人类细胞中的功能以前从未被研究过。 确定。在本提案中，我们将利用小鼠体外和体内败血症的前瞻性临床研究 模型。这些互补的人类和小鼠研究将使我们能够证明临床相关性，同时 还剖析了 IFITM3 在炎症过程中控制 MK 和血小板功能的机制。这些 研究具有转化性和创新性，因为 IFITM3 对内吞作用的调节是细胞内吞作用的关键过程 细胞功能。此前尚未在 MK、血小板或原代细胞中研究过这一点 人体细胞。他们还将首次确定炎症激动剂是否调节转录 以及 MK 和发育中血小板的翻译事件。这项工作将测试一个重要的功能 假设并阐明炎症和脓毒症期间血栓形成的病理生理机制。 该提案对估计数以千计的退伍军人具有直接转化潜力 发展为败血症，并将成为影响更广泛的炎症性疾病的进一步进展的基础 退伍军人人口。

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.