MicroRNA-mediated control of immune responses and tolerance

MicroRNA介导的免疫反应和耐受性控制

• 批准号: 10330540
• 负责人: Li-Fan Lu
• 金额: $ 39.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10330540
• 关键词: Adaptive Immune System; Alleles; Allergens; Animal Experimentation; Autoimmunity; B cell differentiation; B-Lymphocytes; BCL6 gene; Biochemical; Biological; Biological Process; Body Surface; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Lineage; Cells; Cellular Immunity; Cellular biology; ChIP-seq; Data; Development; Disease; Disease model; Ensure; Equilibrium; Family; Foundations; Funding; Future; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Goals; HMGB Proteins; High-Throughput Nucleotide Sequencing; Homeostasis; Human; Humoral Immunities; Hybrids; Immune; Immune System Diseases; Immune Tolerance; Immune response; Immune system; Immunity; Immunologics; Immunoprecipitation; Impairment; In Vitro; Infection; Knowledge; Lead; Mediating; Memory; Methods; MicroRNAs; Modeling; Molecular; Mus; Outcome; Physiological; Pilot Projects; Play; Population; Production; Publishing; RNA; Reaction; Regulation; Regulatory T-Lymphocyte; Research; Role; Seeds; Site; Solid; Structure of germinal center of lymph node; T cell differentiation; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Therapeutic; Thymocyte Selection; Tissues; Translational Research; Untranslated RNA; Up-Regulation; Virus Diseases; Work; adaptive immunity; aged; airway inflammation; arm; cell mediated immune response; combat; crosslink; cytokine; effector T cell; exhaustion; first responder; gain of function; genetic manipulation; immunological status; immunoregulation; in vivo; loss of function; member; miRNA expression profiling; novel; organ growth; response; tool; transcription factor; transcriptome sequencing

Like transcription factors, microRNAs (miRNAs), a class of short regulatory non-coding RNAs known for their role in organ development, cellular differentiation, homeostasis, and function, have been extensively studied for their roles in controlling expression of different sets of genes that dictates the outcome of developmental transitions or cellular activation status of the immune cell populations. Previously, we have identified an important miRNA family, miR-23~27~24 clusters that play a diverse role in regulating the differentiation and function of multiple CD4+ helper T (Th) cell lineages as well as regulatory T (Treg) cells. Our work has shown that proper gene regulation by the miR-23~27~24 in CD4+ T cells is crucial to ensure the optimal balance between immunity and tolerance. Loss of miR-23~27~24 clusters in T cells resulted in dysregulated follicular helper (Tfh) cell responses when mice aged and severe Th2-driven airway inflammation upon challenges of different allergens. On the other hand, excessive expression of members of this miRNA family would also lead to the development of autoimmunity through both promoting the proinflammatory cytokine production by effector T (Teff) cells as well as impairing Treg cell homeostasis and function. Considering that many of the miRNA family targets identified in our previous work are also known to function in other immune cell populations, miR-23~27~24 clusters likely have a broader impact on the immune system beyond their role in regulating CD4+ T cell immunity. Here, we propose a multifaceted study employing genetic, biochemical, immunological approaches and whole animal experimentation to comprehensively examine the molecular and cellular mechanisms underlying miR-23 cluster-mediated immune regulation. In particular, while we will expand our efforts in studying this miRNA family in T cell immunity with a new focus on CD8+ T cell-mediated immune responses, we will also examine their potential new roles in both Tfh cells and B cells that are crucial for establishment of germinal center (GC) reactions and the resultant humoral immunity. Next, by combining RNA-seq, ChIP-seq approaches with newly developed IR-CLASH technology, we will explore the putative molecular mechanisms underlying miR-23 cluster-dependent immune regulation through identification of genes that are regulated in miR-23 cluster-dependent manner and through identification of targets that are directly controlled by miR-23 cluster. Collective, the over-arching goal of the current proposal is to not only establish a powerful model to dissect the molecular orchestration of cellular differentiation, function, and homeostasis in the adaptive immune system but also build a solid foundation with which to target the miR-23~27~24 family to combat infections and a wide array of human immunological diseases.

像转录因子一样 在器官发育，细胞分化，稳态和功能中的作用已被广泛研究 因为它们在控制不同基因的表达中的作用，该基因决定了发展的结果 免疫细胞群体的过渡或细胞激活状态。以前，我们已经确定了 重要的miRNA家族，miR-23〜27〜24个簇在调节分化和 多个CD4+辅助者T（Th）细胞谱系以及调节t（Treg）细胞的功能。我们的工作表明 CD4+ T细胞中miR-23〜27〜24的适当基因调节对于确保最佳平衡至关重要 免疫和耐受性之间。 MiR-23〜27〜24簇在T细胞中的损失导致卵泡失调 当小鼠老化和严重Th2驱动的气道炎症时，助手（TFH）细胞反应 不同的过敏原。另一方面，这个miRNA家族成员的过度表达也将 通过促进促炎细胞因子产生的促炎性细胞因子的产生，导致自身免疫发展 效应子T（TEFF）细胞以及损害Treg细胞稳态和功能。考虑到许多 我们先前工作中确定的miRNA家族靶标也已知在其他免疫细胞中起作用 种群miR-23〜27〜24簇可能对免疫系统产生更大的影响，超出其在其中的作用 调节CD4+ T细胞免疫。在这里，我们提出了一项采用遗传，生化， 免疫学方法和全动物实验以全面检查分子 MiR-23簇介导的免疫调节的基础的细胞机制。特别是，虽然我们会 扩大我们在研究T细胞免疫中研究这种miRNA家族的努力，新的重点是CD8+ T细胞介导的 免疫反应，我们还将检查其在TFH细胞和B细胞中的潜在新作用 用于建立生发中心（GC）反应和由此产生的体液免疫。接下来，结合 RNA-seq，通过新开发的IR-Clash技术的芯片序列方法，我们将探索推定的 通过鉴定，miR-23簇依赖性免疫调节的分子机制 以miR-23簇依赖性方式调节的基因，并通过鉴定目标 直接由miR-23簇控制。集体，当前建议的总体目标不仅是 建立一个强大的模型，以剖析细胞分化，功能和 自适应免疫系统中的体内平衡，但也建立了一个坚实的基础 miR-23〜27〜24家族与感染和各种各样的人类免疫疾病。