microRNA Regulation of T Cell Senescence

T 细胞衰老的 microRNA 调控

• 批准号: 8622024
• 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
• 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/8622024
• 关键词: Accounting; Age; Aging; Antigens; Apoptosis; BCL2 gene; Binding; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Aging; Cell Survival; Cell physiology; Characteristics; Chronic; Clonal Expansion; Data; Deacetylase; Deacetylation; Defect; Distant; Elderly; Enzymes; Epigenetic Process; Event; Exoribonucleases; Feedback; Genes; Health; Herpes zoster disease; Human; IL2 gene; Immune; Immune response; Immune system; Immunity; Individual; Infection; Infectious Agent; Influenza; JUN gene; Lead; Life; Mediating; Memory; Methylation; MicroRNAs; Morbidity - disease rate; Mus; Nucleic Acid Regulatory Sequences; Oncogenes; Oncogenic; Pathway interactions; Pattern; Peptides; Phenotype; Phosphoric Monoester Hydrolases; Population; Production; Protein Dephosphorylation; Publishing; Receptor Activation; Receptor Signaling; Regulation; Signal Pathway; Signal Transduction; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Transcript; Translating; Translations; Vaccination; Western Blotting; age effect; age related; aged; base; cell age; cellular longevity; cytokine; demographics; desensitization; design; improved; in vivo; memory CD4 T lymphocyte; mortality; overexpression; p65; prevent; promoter; protein expression; public health relevance; reconstitution; response; senescence

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（由申请方提供）：衰老免疫系统产生适应性免疫应答的能力降低，影响疫苗接种的有效性，并增加感染的发病率。对外源性或内源性威胁的适应性免疫应答依赖于多样化的T细胞库和抗原特异性T细胞的快速激活和扩增 群体和效应子功能的获得。在研究年龄对CD 4 T细胞功能的影响时，我们已经确定miR 181 a的下降是T细胞老化的特征标志。到目前为止，我们的研究主要集中在双特异性磷酸酶（DUSP）6上，该酶被miR 181 a抑制，因此随着年龄的增长而增加。DUSP 6校准T细胞受体激活阈值，在该阈值下刺激被转化为生产性信号。增加的DUSP 6有助于降低老年T细胞的反应敏感性。miRNA通过抑制基因组的翻译发挥作用，这些基因组通常属于相关途径。目前的建议是基于这样的假设，即miR 181 a和共调节miR 181 b的下降对于理解T细胞衰老具有广泛的重要性，并且具有超出DUSP 6活性增加的后果。除了DUSP 6，我们还将重点关注SIRT 1、BCL-2和TCL 1。DUSP 6和SIRT 1的共同点是它们控制T细胞活化中的负反馈回路。SIRT 1、BCL-2和TCL 1是T细胞存活途径的关键组分。因此，miR 181 a/B的下降导致T细胞表型，其有利于细胞寿命和静止，但以活化和效应子功能为代价。在目标1中，我们将研究控制miR 181 a/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miR 181 a/B随年龄下降的原因，并确定上调表达的方法。目的2将检测年龄对T细胞亚群中SIRT 1、BCL-2和TCL 1表达的影响，并确定蛋白表达的年龄相关变化是否由miR 181 a/B表达程度引起，以及是否可以通过miR 181 a/B过表达逆转。在目标3中，我们将检查miR 181 a/B缺失的功能后果，并确定它们是否可归因于DUSP 6、SIRT 1、TCL 1或BCL-2的过表达。