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）：衰老的免疫系统产生适应性免疫反应的能力降低，损害了疫苗接种的功效并增加了感染的发病率。对外源性或内源性威胁的适应性免疫反应依赖于多样化的 T 细胞库以及抗原特异性 T 细胞的快速激活和扩增群体和效应器功能的获得。在研究年龄对 CD4 T 细胞功能的影响时，我们发现 miR181a 的下降是 T 细胞衰老的一个特征标志。到目前为止，我们的研究主要集中在双特异性磷酸酶 (DUSP) 6，它受到 miR181a 的抑制，因此随着年龄的增长而相应增加。 DUSP6 校准 T 细胞受体激活阈值，在该阈值下刺激会转化为生产信号。 DUSP6 增加会导致老年 T 细胞反应的敏感性降低。 miRNA 通过抑制基因组的翻译来发挥作用，这些基因通常属于相关途径。目前的提议基于这样的假设：miR181a 和共同调节的 miR181b 的下降对于理解 T 细胞衰老具有广泛的重要性，其后果不仅仅是 DUSP6 活性的增加。除了 DUSP6 之外，我们还将重点关注 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组成部分。因此，miR181a/b 的下降会导致 T 细胞表型有利于细胞寿命和静止，但会牺牲激活和效应功能。在目标 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。这些研究的目的是了解是什么导致 miR181a/b 随着年龄的增长而下降，并确定上调表达的方法。目标 2 将检查年龄对 T 细胞亚群中 SIRT1、BCL-2 和 TCL1 表达的影响，并确定与年龄相关的蛋白质表达变化是否由 miR181a/b 表达程度引起，并可以通过 miR181a 逆转/b 过度表达。在目标 3 中，我们将检查 miR181a/b 丢失的功能后果，并确定它们是否可归因于 DUSP6、SIRT1、TCL1 或 BCL-2 的过度表达。