microRNA Regulation of T Cell Senescence

T 细胞衰老的 microRNA 调控

基本信息

批准号：
9197269
负责人：
JORG J GORONZY
金额：
$ 42.99万
依托单位：
PALO ALTO VETERANS INSTIT FOR RESEARCH
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：
2014-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9197269
关键词：
Age Aging Antigens Apoptosis BCL2 gene Binding CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Aging Cell Survival Cell physiology Characteristics Chronic Clonal Expansion DUSP6 protein Data Deacetylase Deacetylation Defect Distant Elderly Enzymes Epigenetic Process Event Exoribonucleases Feedback Genes Genetic Transcription Health Herpes zoster disease Human IL2 gene Immune Immune response Immune system Immunity Individual Infection Infectious Agent Influenza JUN gene Knockout Mice Lead Life Mediating Memory MicroRNAs Morbidity - disease rate Mus Nucleic Acid Regulatory Sequences Oncogenes Oncogenic Pathway interactions Peptides Phenotype Phosphoric Monoester Hydrolases Population Production Protein Dephosphorylation Publishing Receptor Activation Receptor Signaling SIRT1 gene Signal Pathway Signal Transduction T cell regulation T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Testing Transcript Translating Translations Vaccination Western Blotting adaptive immune response age effect age related aged base cellular longevity cytokine demographics desensitization design improved in vivo memory CD4 T lymphocyte methylation pattern mortality overexpression p65 prevent promoter protein expression public health relevance reconstitution response senescence

项目摘要

DESCRIPTION (provided by applicant): The reduced ability of the aging immune system to mount adaptive immune responses compromises the efficacy of vaccinations and increases the morbidity from infections. Adaptive immune responses to exogenous or endogenous threats rely on a diverse T cell repertoire and the rapid activation and expansion of an antigen-specific T cell population and acquisition of effector functions. In studying the effect of age on CD4 T cell function, we have identified a decline in miR181a as a characteristic hallmark of T cell aging. Our studies so far have focused on the dual-specific phosphatase (DUSP) 6 which is repressed by miR181a and therefore reciprocally increases with age. DUSP6 calibrates the T cell receptor activation threshold at which stimulation is translated into a productive signal. Increased DUSP6 contributes to the lowered sensitivity of elderly T cells to respond. miRNAs function by repressing the translation of sets of genes, frequently belonging to related pathways. The current proposal is based on the hypothesis that the decline in miR181a and the co-regulated miR181b is of broad importance to understand T cell aging and has consequences that go beyond increased DUSP6 activity. In addition to DUSP6, we will focus on SIRT1, BCL-2, and TCL1. What DUSP6 and SIRT1 have in common is that they control negative feedback loops in T cell activation. SIRT1, BCL-2 and TCL1 are critical components of T cell survival pathways. The decline in miR181a/b therefore results in a T cell phenotype that favors cellular longevity and quiescence at the expense of activation and effector function. In Aim 1, we will examine the epigenetic, transcriptional and post-transcriptional mechanisms that control miR181a/b expression. The objectives of these studies are to understand what drives the decline in miR181a/b with age and to identify means to upregulate expression. Aim 2 will examine the influence of age on the expression of SIRT1, BCL-2, and TCL1 in T cell subsets and determine whether age-related changes in protein expression are caused by the degree of miR181a/b expression and can be reversed by miR181a/b overexpression. In Aim 3, we will examine the functional consequences of miR181a/b loss, and we will determine whether they can be attributed to the overexpression of DUSP6, SIRT1, TCL1 or BCL-2.

描述（由申请人提供）：衰老免疫系统安装适应性免疫反应的能力降低了疫苗接种的疗效并增加了感染的发病率。对外源或内源性威胁的自适应免疫反应依赖于多种T细胞库以及抗原特异性T细胞的快速激活和扩展人口和效应功能的获取。在研究年龄对CD4 T细胞功能的影响时，我们确定MiR181a的下降是T细胞衰老的特征标志。迄今为止，我们的研究集中在双特异性磷酸酶（DUSP）6上，该酶受到miR181a的抑制，因此随着年龄的增长而相互增加。 DUSP6校准T细胞受体激活阈值，在该刺激中，刺激被转化为生产信号。 DUSP6增加有助于老年T细胞的敏感性降低。 miRNA通过抑制经常属于相关途径的基因集的翻译来函数。当前的提议基于以下假设：MiR181a和共同调节的MiR181b的下降对于了解T细胞衰老并且产生超出DUSP6活性的后果至关重要。除了DUSP6，我们还将专注于SIRT1，BCL-2和TCL1。 DUSP6和SIRT1的共同点是它们控制T细胞激活中的负反馈回路。 SIRT1，BCL-2和TCL1是T细胞存活途径的关键成分。因此，miR181a/b的下降会导致T细胞表型，该表型有利于细胞的寿命和静止，而以激活和效应功能为代价。在AIM 1中，我们将检查控制miR181a/b表达的表观遗传，转录和转录后机制。这些研究的目标是了解什么会随着年龄的增长而导致miR181a/b的下降，并确定上调表达的方法。 AIM 2将检查年龄对T细胞亚群中SIRT1，BCL-2和TCL1表达的影响，并确定蛋白质表达与年龄相关的变化是否由miR181a/b表达的程度引起，并且可以通过miR181a/b的过表达逆转。在AIM 3中，我们将检查MIR181A/B损失的功能后果，我们将确定它们是否可以归因于DUSP6，SIRT1，TCL1或BCL-2的过表达。