Platelet Reprogramming During Inflammation

炎症和脓毒症的特征在于跨越止血、炎性 和免疫连续体血栓形成是脓毒症的常见并发症，导致不良结局 包括器官衰竭和死亡这种破坏性的失调宿主反应的重要性在于 数据表明，包括退伍军人在内的所有医院死亡中有一半可能是由于 到败血症新出现的证据支持这一概念，即血小板反应失调介导了 炎症期间的病理生理学。尽管如此，分子机制和功能的后果， 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 炎症过程中的重编程”将确定炎症激动剂的新途径， 干扰素（IFN）调节血小板及其亲本细胞巨核细胞（MK）中的基因表达。我们 初步研究已经确定干扰素诱导的跨膜蛋白3（IFITM3）的表达， 在脓毒症期间在人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。调控 以及IFITM3在MK和血小板中的功能，或者任何其他人类细胞中的功能，以前从未被 鉴定在本提案中，我们将利用体外和体内小鼠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， 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 研究是翻译和创新的，因为IFITM3调节内吞作用，这是一个关键的过程， 细胞功能这在以前没有在MK、血小板或原发性血小板中研究过。 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和发育中的血小板中的翻译事件。这项工作将测试一个重要的功能 阐明炎症和脓毒症时血栓形成病理生理机制。 这项提案对成千上万的退伍军人有直接的转化潜力， 发生败血症，并将成为更广泛影响的炎症性疾病的额外进展的基础。 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.