Platelet Immune Responses in Aging and Influenza

衰老和流感中的血小板免疫反应

基本信息

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
项目类别：
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

项目摘要

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）：血小板作为动态和多功能免疫效应细胞出现，可介导宿主对包括流感在内的呼吸道病毒感染的反应。在老年人中，流感感染很常见，并引起大量的发病率和死亡率。我们的赠款（标题为“衰老和流感中的血小板免疫反应”将检查与年龄相关的新发现的血小板免疫蛋白的变化，以及受损反应如何导致不良临床结果。这种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感染性。 IFITM家族成员以前尚未在人血小板中描述。我们的具体目的和假设是基于丰富的初步数据库，表明老年人的血小板在流感感染期间和流感疫苗后的IFITM表达降低。我们还发现，无法上调IFITM蛋白表达与与流感相关死亡率的风险增加相关。在我们的初步研究中，有证据表明IFITM的表达发生在血小板中的转录和转录后检查点前体（例如，巨核细胞）和成熟的血小板。在此应用中，我们将在流感感染和流感疫苗接种后确定，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诱导中与年龄相关的损害是否有助于流感相关的疾病严重程度和死亡率。此外，我们将剖析人血小板中IFITM表达的机制和模式，并模拟源自年轻人和年长人类受试者的巨核细胞。虽然我们将详细研究IFITM家族成员，但我们还将使用深层RNA测序（RNA-SEQ）来鉴定老年人改变的血小板和巨核细胞中其他候选免疫调节基因。通过RNA-Seq确定的候选者将在消息，蛋白质和/或活动水平上进行深入研究。这些调查是最早表征的研究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，因此我们的发现将立即具有临床相关性。我们的多学科团队将年轻和高级调查员，临床医生和基础科学家团结起来。建立了所有技术和工具，并且已经建立了现实，我们已经验证了范式转移，卧铺到床的发现研究的记录。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测，并定义调节老年人流感诱导的血小板免疫反应的新机制。