MicroRNAs in Tissue-resident memory T cells

组织驻留记忆 T 细胞中的 MicroRNA

• 批准号: 10609026
• 负责人: ANDREW W GRIMSON
• 金额: $ 22.34万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-11 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609026
• 关键词: Adaptive Immune System; Adult; Animals; Antigens; B-Lymphocytes; Biological Assay; Bone Marrow; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Characteristics; Circulation; Data; Development; Event; Exhibits; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genomic approach; Genomics; Goals; Human; Human Biology; Immune response; Immune system; Immunity; Immunologic Memory; Individual; Infection; Intestines; Lung; Maintenance; Maps; Measures; Mediating; Memory; Messenger RNA; MicroRNAs; Mus; Neonatal; Organ; Pathway interactions; Pattern; Phenotype; Play; Population; Post-Transcriptional Regulation; Prevalence; Primary Infection; Property; RNA; Regulation; Regulator Genes; Regulatory Pathway; Repression; Role; Running; SELL gene; Sampling; Small RNA; Specific qualifier value; Specificity; Spleen; T cell reconstitution; T cell response; T memory cell; T-Lymphocyte; Tissue Survival; Tissues; Untranslated RNA; Validation; adaptive immunity; cellular transduction; computerized tools; effector T cell; experimental study; gain of function; gene regulatory network; genomic data; human disease; human tissue; lymph nodes; miRNA expression profiling; mouse model; neonate; next generation sequencing; pathogen; phenotypic biomarker; posttranscriptional; programs; reconstitution; response; secondary infection; stem cells; tissue resident memory T cell; transcription factor; transcriptome; transcriptome sequencing

Project Summary / Abstract A defining feature of the adaptive immune system is the existence of specialized memory cells, which originate in response to a primary infection, and provide durable immunity during subsequent infections. Multiple types of memory T cells exist, with characteristic patterns of localization and functional specialization. Tissue- resident memory (TRM) T cells reside in each adult tissue and organ provide localized immunological memory and response to infection. Understanding the gene regulatory programs that specify TRM cells and enable their functional specialization is a major goal, and recent discoveries have revealed the identities of several transcription factors that play important roles in TRM T cells. Here, we propose to systematically examine whether microRNAs contribute to TRM cell gene regulatory programs, using human and mouse cells. MicroRNAs (miRNAs), a class of small regulatory RNAs, represent an essential additional layer of gene regulation, which act to repress target mRNAs post-transcriptionally. Notably, the majority of human genes are regulated by miRNAs, and the vast majority of gene regulatory pathways are believed to incorporate miRNAs. In the immune system, many critical events are regulated by miRNAs, however, no studies have investigated miRNAs in the context of TRM cells. In Aim I, we will use genomic approaches to identify miRNAs that are preferentially expressed in human and mouse TRM T cells, compared to central memory and effector memory T cells, and computational tools to define the miRNAs that are acting to regulate the transcriptome of TRM T cells. In Aim II, we will use mouse models to functionally validate roles for specific miRNAs in TRM T cells. Completion of these Aims will break new ground by generating comprehensive profiles of all miRNAs and their targeting signatures in diverse human and mouse TRM cell populations. This study is a pivotal first step towards understanding how specific miRNAs can be used to promote more durable immunity by increasing the formation and survival of TRM cells.

项目概要/摘要 适应性免疫系统的一个决定性特征是存在专门的记忆细胞，这些细胞起源于 应对初次感染，并在后续感染期间提供持久的免疫力。多种类型 存在大量记忆 T 细胞，具有定位和功能专门化的特征模式。组织- 驻留记忆 (TRM) T 细胞驻留在每个成人组织和器官中，提供局部免疫记忆 和对感染的反应。了解指定 TRM 细胞并启用的基因调控程序 他们的功能专业化是一个主要目标，最近的发现揭示了几个人的身份 在 TRM T 细胞中发挥重要作用的转录因子。在此，我们建议系统地考察 使用人类和小鼠细胞，microRNA 是否有助于 TRM 细胞基因调控程序。 MicroRNA (miRNA) 是一类小调控 RNA，代表基因的重要附加层 调节，其作用是在转录后抑制目标 mRNA。值得注意的是，大多数人类基因 受 miRNA 调控，绝大多数基因调控途径被认为包含 miRNA。 在免疫系统中，许多关键事件是由 miRNA 调节的，然而，还没有研究对此进行调查 TRM 细胞中的 miRNA。在目标 I 中，我们将使用基因组方法来识别以下 miRNA： 与中枢记忆和效应记忆相比，优先在人和小鼠 TRM T 细胞中表达 T 细胞和计算工具来定义调节 TRM T 转录组的 miRNA 细胞。在 Aim II 中，我们将使用小鼠模型来功能验证特定 miRNA 在 TRM T 细胞中的作用。 这些目标的完成将通过生成所有 miRNA 及其相关的综合图谱来开辟新天地。 针对不同人类和小鼠 TRM 细胞群的特征。这项研究是关键的第一步 旨在了解如何使用特定的 miRNA 通过增加 TRM细胞的形成和存活。