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

干扰素诱导的跨膜蛋白 3 (IFITM3) 在衰老炎症过程中调节血栓形成

• 批准号: 9914189
• 负责人: Robert A Campbell
• 金额: $ 9.98万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914189
• 关键词: Admission activity; Adult; Age; Aging; Agonist; Biology; Blood Platelets; Cause of Death; Cell Nucleus; Cell physiology; Cells; Cessation of life; Complication; Critical Illness; Data; Deep Vein Thrombosis; Dissection; Elderly; Endocytosis; Event; FRAP1 gene; Fibrinogen; Gene Expression; Gene Expression Regulation; Genetic Transcription; Hemostatic Agents; Hospitals; Human; Hyperactive behavior; Immune response; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inherited; Integral Membrane Protein; Intensive Care; Interferons; Invaded; Knowledge; Link; Lung; Mediating; Megakaryocytes; Molecular; Morbidity - disease rate; Mus; Organ failure; Parents; Pathway interactions; Patients; Physiological; Predisposition; Process; Proteins; Proteome; Regulation; Risk; Risk Factors; Sepsis; Stress; Syndrome; Testing; Thrombosis; Time; Toxin; United States; Work; aged; aging population; base; clinically relevant; human old age (65+); in vivo; innovation; mortality; mouse model; older patient; pathogen; platelet function; response; septic; septic patients; stressor; systemic inflammatory response; transcriptome; young adult

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.

项目摘要/摘要 衰老伴随着对生理压力的耐受性降低，这促进了易感性的增加。 到炎症性疾病。严重的疾病，如败血症，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意义在于 数据显示，所有医院重症监护病房的入院人数中，有一半来自年龄超过 65，并可能归因于感染。新出现的证据支持这样一种观点，即调节失调的血小板 炎症过程中的功能调节损害性宿主反应。然而，分子机制 衰老和炎症过程中调节异常的血小板功能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(IFITM3)” 《在衰老的炎症过程中调节血栓形成》将确定炎症激动剂， 包括干扰素(IFN)，调节血小板及其母细胞巨核细胞(MK)的基因表达， 在衰老过程中。我们的初步研究已经证实，IFITM3在人类体内的表达被强烈地诱导 败血症期间的血小板，这是一种全身炎症性疾病。有趣的是，老年人和老年人的巨噬细胞和血小板 与年轻对照组相比，小鼠在干扰素刺激后表达更多的IFITM3。我们的数据表明，IFITM3 促进巨噬细胞和血小板的纤维蛋白原内吞，导致血小板高反应性和血栓形成。我们的 研究结果还表明，在衰老和炎症应激期间，哺乳动物雷帕霉素途径的靶点 被激活，触发IFITM3合成和血栓形成。IFITM3在MKs和MKs中的表达及功能 血小板及其受mTOR的调节是一个以前未被研究过的途径。在这项提议中，我们将结对 对老年和年轻败血症患者进行的体外和体内使用老龄小鼠模型的研究。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 炎症过程中IFITM3调节MK和血小板功能的机制。这些研究是 翻译和创新，如IFITM3调节内吞作用，这是一个对细胞功能至关重要的过程， 之前还没有在巨噬细胞、血小板或任何原代人类细胞中进行过研究。他们 还将首次确定衰老是否改变炎性激动剂对转录的影响 以及巨噬细胞和血小板中的转译事件。这项工作将检验一个重要的功能假说和 阐明炎症过程中血栓形成老化的病理生理机制。这项建议具有 老年脓毒症患者的翻译潜力，也将发现连接的新途径 衰老过程中的血栓形成和炎症。