Platelet Reprogramming During Inflammation

炎症和脓毒症的特征是机体反应失调，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。这种破坏性的失调宿主反应的意义在于 数据显示，包括退伍军人在内的所有医院死亡人数的一半可能是 致败血症。新出现的证据支持这样一个概念，即调节失调的血小板反应介导了 炎症期间的病理生理学。尽管如此，其分子机制和功能后果 脓毒症时的血小板功能失调仍未完全了解。我们的提案，题为《血小板 炎症过程中的重新编程“将确定炎症激动剂包括， 干扰素(IFN)调节血小板及其母细胞巨核细胞(MK)的基因表达。我们的 初步研究证实，干扰素诱导的跨膜蛋白3(IFITM3)的表达 在脓毒症期间在人的血小板中被强烈诱导。此外，我们的数据表明，IFITM3上调 纤维蛋白原在巨噬细胞和血小板内吞，导致血小板高反应性和血栓形成。这项规定 在巨噬细胞和血小板中，或在任何其他人类细胞中，IFITM3的功能是前所未有的 已确认身份。在这项提案中，我们将利用体内和体外对脓毒症小鼠的前瞻性临床研究。 模特们。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在炎症过程中调节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。这在以前还没有在巨噬细胞、血小板或--就此而言--初级患者身上进行过研究 人类细胞。他们还将首次确定炎性激动剂是否调节转录 巨噬细胞和发育中的血小板中的转译事件。这项工作将测试一个重要的功能 提出并阐明炎症和败血症时血栓形成的病理生理机制。 这项提议对数以千计的退伍军人来说既有直接的翻译潜力，估计 发展成脓毒症，并将为更广泛影响的炎症性疾病的进一步进展奠定基础 退伍军人群体。

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.