Platelet Immune Responses in Aging and Influenza

衰老和流感中的血小板免疫反应

• 批准号: 8625156
• 负责人: Matthew Thomas Rondina
• 金额: $ 37.24万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8625156
• 关键词: Accounting; Aging; Agonist; Antibody Formation; Blood Platelets; Cells; Cellular Membrane; Clinical; Cytoplasmic Granules; Data; Development; Disease; Effector Cell; Elderly; Family; Family member; Functional disorder; Gene Expression Profile; Genes; Grant; Human; Immune; Immune response; Impairment; Influenza; Influenza A Virus, H1N1 Subtype; Influenza vaccination; Integral Membrane Protein; Interferons; Investigation; Maintenance; Mediating; Megakaryocytes; Membrane; Modeling; Morbidity - disease rate; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Post-Transcriptional Regulation; Predisposition; Prevention; Protein Family; Proteins; Proteome; RNA Sequences; Records; Research; Research Personnel; Risk; Role; Scientist; Severity of illness; Techniques; Viral; Virus Diseases; Virus Replication; adverse outcome; age related; base; bench to bedside; clinically relevant; high risk; human IFITM1 protein; human subject; immune function; immunosenescence; improved; influenzavirus; mortality; older patient; prevent; protein expression; public health relevance; respiratory; response; tool; transcriptome sequencing

DESCRIPTION (provided by applicant): Platelets are emerging as dynamic and versatile immune effector cells that mediate host responses to respiratory viral infections, including influenza. In the elderly, influenza infections are common and cause substantial morbidity and mortality. Our grant, entitled "Platelet Immune Responses in Aging and Influenza" will examine age-related changes in newly-discovered platelet immune proteins and how impaired responses contribute to adverse clinical outcomes. This family of proteins, the interferon-induced transmembrane proteins (IFITMs), prevents influenza viral replication and infectivity. IFITM family members have not previously been described in human platelets. Our specific aims and hypotheses are based on a rich pool of preliminary data demonstrating that platelets from older adults have diminished expression of IFITMs during influenza infection and following influenza vaccination. We also found that the inability to upregulate IFITM protein expression correlates with an increased risk of influenza-related mortality. In our preliminary studies, there is evidenc that expression of IFITM occurs at transcriptional and post-transcriptional checkpoints in platelet precursors (e.g., megakaryocytes) and mature platelets. In this application, we will determine, in settings of influenza infection and following influenza vaccination, whether aging alters the induction of IFITM proteins in human platelets. We will also establish whether age-related impairments in IFITM induction contribute to influenza-related illness severity and mortality. Moreover, we will dissect the mechanisms and patterns of IFITM expression in human platelets and model megakaryocytes derived from young and older human subjects. While we will investigate IFITM family members in detail, we will also use deep RNA-sequencing (RNA-seq) to identify other candidate immunomodulatory genes in platelets and megakaryocytes that are altered in older adults. Candidates identified by RNA-seq will be examined in-depth at the message, protein, and/or activity level. These investigations are the first studies to characterize IFITMs in megakaryocytes and platelets. As our investigations will be accomplished using human subjects and primary human cells, our findings will have immediate clinical relevance. Our multi-disciplinary team unites young and senior investigators, clinicians, and basic scientists. All techniques and tools are established and in place and we have proven track records of paradigm-shifting, bench-to-bedside discovery research. Thus, we are poised to determine how aging alters immune sensing by platelets and megakaryocytes and define new mechanisms regulating influenza-induced platelet immune responses in the elderly.

描述（由申请人提供）：血小板正在成为一种动态且多功能的免疫效应细胞，可介导宿主对呼吸道病毒感染（包括流感）的反应。在老年人中，流感感染很常见，并导致很高的发病率和死亡率。我们的拨款题为“衰老和流感中的血小板免疫反应”，将研究新发现的血小板免疫蛋白与年龄相关的变化，以及受损的反应如何导致不良的临床结果。这个蛋白质家族，即干扰素诱导的跨膜蛋白 (IFITM)，可防止流感病毒复制和感染性。此前尚未在人类血小板中描述过 IFITM 家族成员。我们的具体目标和假设基于丰富的初步数据，这些数据表明老年人的血小板在流感感染期间和流感疫苗接种后 IFITM 的表达减少。我们还发现，无法上调 IFITM 蛋白表达与流感相关死亡风险增加相关。在我们的初步研究中，有证据表明 IFITM 的表达发生在血小板的转录和转录后检查点 前体细胞（例如巨核细胞）和成熟血小板。在此应用中，我们将确定在流感感染和流感疫苗接种后，衰老是否会改变人类血小板中 IFITM 蛋白的诱导。我们还将确定 IFITM 诱导中与年龄相关的损伤是否会导致流感相关疾病的严重程度和死亡率。此外，我们将剖析来自年轻和老年受试者的人类血小板和模型巨核细胞中 IFITM 表达的机制和模式。虽然我们将详细研究 IFITM 家族成员，但我们还将使用深度 RNA 测序 (RNA-seq) 来识别血小板和巨核细胞中在老年人中发生改变的其他候选免疫调节基因。通过 RNA-seq 鉴定的候选者将在信息、蛋白质和/或活性水平上进行深入检查。这些调查是第一个表征 巨核细胞和血小板中的 IFITM。由于我们的研究将使用人类受试者和原代人类细胞来完成，因此我们的研究结果将具有直接的临床意义。我们的多学科团队将年轻和资深的研究人员、临床医生和基础科学家团结在一起。所有技术和工具均已建立并到位，我们在范式转变、从实验室到临床的发现研究方面拥有经过验证的跟踪记录。因此，我们准备确定衰老如何改变血小板和巨核细胞的免疫感应，并定义调节老年人流感诱导的血小板免疫反应的新机制。