Interferon-Induced Transmembrane Protein 3 (IFITM3) Regulates Thrombosis During Inflammation in Aging

项目总结/摘要 衰老伴随着对生理压力的耐受性下降，这促进了易感性的增加 炎症性疾病。严重的疾病，如败血症，disporrhoea影响65岁以上的人， 导致老年人发病率和死亡率增加。血栓形成是脓毒症的常见并发症， 导致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 数据显示，所有医院重症监护病房的一半都是来自年龄超过30岁的人。 65，可能是感染所致。新出现的证据支持血小板失调的概念， 功能介导炎症期间的有害宿主反应。尽管如此， 在衰老和炎症过程中血小板功能失调的功能后果仍然存在 不完全理解。我们的提案题为“干扰素诱导的跨膜蛋白3（IFITM 3）”， 调节衰老炎症过程中的血栓形成”将确定炎症激动剂， 包括干扰素（IFN），调节血小板及其亲本细胞巨核细胞（MK）中的基因表达， 在衰老。我们的初步研究已经确定IFITM 3的表达在人类中被强烈诱导， 败血症是一种全身性炎症性疾病。有趣的是，来自老年人和老年人的MK和血小板 与年轻的对照组相比，小鼠在IFN刺激后表达更多的IFITM 3。我们的数据表明IFITM 3 促进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。我们 研究结果还表明，在衰老和炎症应激期间，雷帕霉素途径的哺乳动物靶点 被激活，触发IFITM 3合成和血栓形成。IFITM 3在巨噬细胞中的表达及功能 血小板及其通过mTOR的调节是先前未检测的途径。在这个提案中，我们将结合 在老年和年轻脓毒症患者中使用老年小鼠进行体外和体内小鼠模型研究。这些 互补的人类和小鼠研究将使我们能够建立临床相关性，同时也解剖了 IFITM 3在炎症期间控制MK和血小板功能的机制。这些研究 作为IFITM 3调节内吞作用的翻译和创新，内吞作用是细胞功能的关键过程， 以前没有在MK、血小板或任何原代人类细胞中进行过研究。他们 这也将首次确定衰老是否会改变炎症激动剂对转录的影响， 和血小板中的翻译事件。这项工作将测试一个重要的功能假设， 阐明炎症过程中血栓形成和衰老的病理生理机制。这一建议 翻译潜力的老年患者脓毒症，也将发现新的途径， 血栓形成和炎症。

PROJECT SUMMARY/ABSTRACT Aging is accompanied by a decreased tolerance to physiological stress, which promotes increased susceptibility to inflammatory illnesses. Critical illnesses such as sepsis, disportionately effect people over the age of 65, leading to increased morbidity and mortality in older adults. Thrombosis is a common complication from sepsis, contributing to organ failure and death. The significance of this devastating dysregulated host response is demonstrated by data showing half of all hospital intensive care admissions are from individuals over the age of 65 and may be attributed to infection. Emerging evidence supports the concept that dysregulated platelet functions mediate the injurious host response during inflammation. Nevertheless, the molecular mechanisms and functional consequences of dysregulated platelet functions during aging and inflammation remain incompletely understood. Our proposal, entitled “Interferon-Induced Transmembrane Protein 3 (IFITM3) Regulates Thrombosis During Inflammation in Aging” will identify new pathways by which inflammatory agonists, including interferons (IFNs), regulate gene expression in platelets and their parent cell, the megakaryocyte (MK), in aging. Our preliminary studies have identified that the expression of IFITM3 is robustly induced in human platelets during sepsis, a systemic inflammatory illness. Interestingly, MKs and platelets from aged human and mice express more IFITM3 after IFN stimulation compared to younger controls. Our data suggest that IFITM3 promotes fibrinogen endocytosis in MKs and platelets, leading to platelet hyperreactivity and thrombosis. Our findings also suggest that in aging and during inflammatory stress, the mammalian target of rapamycin pathway is activated, triggering IFITM3 synthesis and thrombosis. The expression and function of IFITM3 in MKs and platelets and its regulation by mTOR is a pathway not previously examined. In this proposal, we will couple studies in older and younger septic patients with in vitro and in vivo murine models using aged mice. These complementary human and murine studies will allow us to establish 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, has not previously been studied in MKs, platelets, or – for that matter - any primary human cells. They will also determine for the first time whether aging alters the effect of inflammatory agonists on transcriptional and translational events in MKs and platelets. This work will test an important functional hypothesis and clarify pathophysiologic mechanisms of thrombosis aging during inflammation. This proposal has translational potential for older patients with sepsis, and also will uncover new pathways linking thrombosis and inflammation in aging.