microRNA Regulation of T Cell Senescence

T 细胞衰老的 microRNA 调控

• 批准号: 10318961
• 负责人: JORG J GORONZY
• 金额: $ 53.72万
• 依托单位: MAYO CLINIC ROCHESTER
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318961
• 关键词: Age; Antibodies; BCL6 gene; Binding; CD4 Positive T Lymphocytes; Cell Aging; Cell Cycle; Cell Differentiation process; Cells; Characteristics; Chromatin; DUSP6 protein; Data; Defect; Development; Enhancers; FOXO1A gene; Failure; Gene Expression; Gene Expression Profile; Gene Silencing; Generations; Genes; Genetic Transcription; Glycolysis Inhibition; Goals; Helper-Inducer T-Lymphocyte; Histones; Human; Immunologic Memory; Impairment; In Vitro; Individual; Intervention; MicroRNAs; Modern Medicine; Molds; Mus; Nucleosomes; Older Population; Pathway interactions; Pattern; Pharmacology; Phosphoric Monoester Hydrolases; Production; Proliferating; Proteome; Proto-Oncogene Proteins c-akt; Receptor Activation; Receptor Signaling; Regulatory Pathway; SIRT1 gene; Shapes; Signal Pathway; Signal Transduction; Structure; Supporting Cell; T cell differentiation; T cell regulation; T cell response; T memory cell; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Transcription Factor AP-1; Transcriptional Regulation; Vaccination; WNT Signaling Pathway; XCL1 gene; YY1 Transcription Factor; base; cellular transduction; design; effector T cell; improved; in vivo Model; memory CD4 T lymphocyte; overexpression; prevent; pri-miRNA; reconstitution; transcription factor; transcriptome; vaccine response

PROJECT SUMMARY / ABSTRACT Generation of protective vaccine responses, governed by the successful generation of T follicular helper cells and long-lived memory T cells, is increasingly impaired with age. Since microRNAs are a major regulator of the T cell proteome, we hypothesized that age-associated changes in the expression of microRNAs contribute to the defects that are seen with T cell aging. MicroRNAs are known to concomitantly reduce expression of many target molecules, frequently belonging to specific functional modules. While the effect on each of these molecules is generally small, the concerted activity on signaling and transcription factor networks can have major effects. MicroRNAs that are known to be are dynamically regulated during T cell differentiation include miR-181a and miR-21. While miR-181a expression declines with T cell differentiation, miR-21 shows the opposite pattern being higher in effector than in naïve CD4 T cells. For both miRNAs, naïve CD4 T cells from older individuals reflect a state of higher differentiation with decrease in miR181a and increase in miR21 expression. miR-181a is known as a rheostat of T cell receptor signaling thresholds, and indeed older naïve T cells are less responsive to stimulation due to the loss of miR-181a and the associated overexpression of dual specific phosphatase 6. In preliminary studies, we have shown that miR-21 selects against T follicular helper cell differentiation. The current proposal aims at identifying the pathways controlled by these microRNAs with the ultimate goal to either target these microRNAs or the pathways that they regulate to improve immune memory in older individuals after vaccination. In Aim 1, we propose to examine how the shift in miR-181a and miR-21 expression with age selects against the development of transcriptional signatures characteristic of T follicular helper cells and T memory cells. Specifically, we will examine how these microRNAs influence transcription factor networks including FOXO, AP1, BLIMP, BCL6 and TCF1 that are important for T follicular helper and T memory cell differentiation. In Aim 2, we examine consequences of reduced miR-181a expression on the transcription of histone genes and determine the consequences of reduced histones on the nucleosome organization of effector and memory T cells and their ability to proliferate and survive. Aim 3 will examine whether transcription of pri-miR-21 and/or pri-miR-181a can be targeted to improve T cell responses. Based on preliminary studies on transcriptional regulation of these pri-miRNAs, activation of WNT signaling and inhibition of AP1 activity emerge as candidate interventions to restore miR-181a1 and reduce miR-21 expression.

项目摘要 /摘要 由T卵泡细胞成功产生的受保护疫苗反应的产生 并且长寿的记忆T细胞随着年龄的增长而越来越受损。由于microRNA是 T细胞蛋白质组，我们假设与年龄相关的microRNAS表达变化有助于 T细胞衰老看到的缺陷。已知MicroRNA同时降低了许多 靶分子，经常属于特定功能模块。而对每个的影响 分子通常很小，信号传导和转录因子网络的一致活动可以具有 主要影响。在T细胞分化过程中，已知已知已知的microRNA包括 miR-181a和miR-21。而miR-181a的表达随T细胞分化而下降，而miR-21显示了 相反的模式比幼稚的CD4 T细胞更高。对于这两个miRNA，来自幼稚的CD4 T细胞 老年人反映了较高分化的状态，而miR181a的降低并增加了miR21 表达。 miR-181a被称为T细胞受体信号传导阈值的阻尼斯特，实际上是较早的幼稚T 由于miR-181a的丧失和双重表达，细胞对刺激的反应较小 特定的磷酸酶6。在初步研究中，我们表明miR-21选择针对T卵泡辅助器 细胞分化。当前的提案旨在确定这些microRNA控制的途径 针对这些microRNA或它们调节以改善免疫力的途径的最终目标 疫苗接种后老年人的记忆。在AIM 1中，我们建议研究mir-181a的转变和 MiR-21随着年龄的选择而反对转录特征的发展特征的MiR-21表达 Follic辅助细胞和T记忆细胞。具体而言，我们将研究这些microRNA如何影响 转录因子网络在内 助手和T记忆细胞分化。在AIM 2中，我们检查了MiR-181a减少的后果 对组蛋白基因转录的表达，并确定组蛋白减少的后果 核小体的效应子和记忆T细胞的组织及其增殖和生存的能力。目标3意志 检查PRI-MIR-21和/或PRI-MIR-181A是否可以针对T细胞反应的转录。 基于这些PRI-MIRNA的转录调控的初步研究，Wnt信号的激活 并抑制AP1活性作为候选干预措施恢复miR-181a1并减少miR-21 表达。