Platelet Immune Responses in Aging and Influenza

衰老和流感中的血小板免疫反应

• 批准号: 8852034
• 负责人: Matthew Thomas Rondina
• 金额: $ 34.99万
• 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/8852034
• 关键词: Accounting; Aging; Agonist; Antibody Response; Blood Platelets; Cells; Cellular Membrane; Clinical; Cytoplasmic Granules; Data; Development; Disease; Effector Cell; Elderly; Family; Family member; Functional disorder; Gene Expression Profile; Genes; Grant; Health; 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; differential expression; high risk; human IFITM1 protein; human subject; immune function; immunosenescence; improved; influenzavirus; mortality; older patient; prevent; protein expression; 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(申请人提供)：血小板正在成为动态和多功能的免疫效应细胞，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，并导致相当大的发病率和死亡率。我们的赠款题为“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，以及反应受损如何导致不利的临床结果。这一蛋白质家族是干扰素诱导的跨膜蛋白(IFITM)，可防止流感病毒复制和传染性。IFITM家族成员以前从未在人类血小板中被描述过。我们的具体目标和假设基于大量的初步数据，这些数据表明，在流感感染期间和接种流感疫苗后，老年人的血小板中IFITM的表达减少。我们还发现，不能上调IFITM蛋白的表达与流感相关死亡的风险增加相关。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(如巨核细胞)和成熟的血小板。在这项应用中，我们将确定在流感感染和接种流感疫苗后，衰老是否会改变人血小板中IFITM蛋白的诱导。我们还将确定IFITM诱导中年龄相关的损害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IFITM在人血小板和来自年轻人和老年人的模型巨核细胞中的表达机制和模式。虽然我们将详细研究IFITM家族成员，但我们也将使用深度RNA测序(RNA-seq)来识别在老年人中改变的血小板和巨核细胞中的其他候选免疫调节基因。由RNA-SEQ确定的候选者将在信息、蛋白质和/或活动水平上进行深入审查。这些调查是第一次对 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，我们的发现将具有直接的临床意义。我们的多学科团队团结了年轻和资深的研究人员、临床医生和基础科学家。所有的技术和工具都已建立和到位，我们已经证明了范式转换、从工作台到床边发现研究的跟踪记录。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知，并定义调控流感诱导的老年人血小板免疫反应的新机制。