microRNA Regulation of T Cell Senescence

T 细胞衰老的 microRNA 调控

• 批准号: 10435599
• 负责人: JORG J GORONZY
• 金额: $ 54.59万
• 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/10435599
• 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.

项目概要/摘要 保护性疫苗反应的产生，由滤泡辅助 T 细胞的成功产生控制 长寿命记忆 T 细胞随着年龄的增长而日益受损。由于 microRNA 是 T 细胞蛋白质组，我们假设与年龄相关的 microRNA 表达变化有助于 T 细胞老化时出现的缺陷。已知 MicroRNA 会同时减少许多基因的表达 目标分子，通常属于特定的功能模块。虽然对每一个的影响 分子通常很小，信号传导和转录因子网络上的协同活动可以具有 主要影响。已知在 T 细胞分化过程中受到动态调节的 MicroRNA 包括 miR-181a 和 miR-21。虽然 miR-181a 表达随着 T 细胞分化而下降，但 miR-21 显示 相反的模式是效应细胞高于初始 CD4 T 细胞。对于这两种 miRNA，来自幼稚 CD4 T 细胞 老年人反映了较高的分化状态，miR181a 减少，miR21 增加 表达。 miR-181a 被称为 T 细胞受体信号阈值的变阻器，并且确实是较老的幼稚 T 由于 miR-181a 的缺失和相关的双重过表达，细胞对刺激的反应较差 特异性磷酸酶 6。在初步研究中，我们已经表明 miR-21 针对滤泡辅助 T 进行选择 细胞分化。目前的提案旨在确定这些 microRNA 控制的途径 最终目标是针对这些 microRNA 或它们调节的途径以改善免疫 老年人接种疫苗后的记忆力。在目标 1 中，我们建议检查 miR-181a 和 miR-181a 的转变如何 miR-21的表达随着年龄的增长而选择对抗T细胞转录特征的发展 滤泡辅助细胞和T记忆细胞。具体来说，我们将研究这些 microRNA 如何影响 转录因子网络包括 FOXO、AP1、BLIMP、BCL6 和 TCF1，对滤泡 T 细胞很重要 辅助细胞和T记忆细胞分化。在目标 2 中，我们研究了 miR-181a 减少的后果 表达对组蛋白基因转录的影响，并确定组蛋白减少对组蛋白基因转录的影响 效应 T 细胞和记忆 T 细胞的核小体组织及其增殖和存活的能力。目标3将 检查 pri-miR-21 和/或 pri-miR-181a 的转录是否可以靶向改善 T 细胞反应。 基于对这些 pri-miRNA 转录调控的初步研究，WNT 信号的激活 和抑制 AP1 活性成为恢复 miR-181a1 和减少 miR-21 的候选干预措施 表达。