MicroRNAs regulate skin Langerhans cells

MicroRNA 调节皮肤朗格汉斯细胞

• 批准号: 10250383
• 负责人: Li Zhou
• 金额: $ 32.12万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250383
• 关键词: Adult; Affect; Bioinformatics; Biology; Birth; C-Type Lectins; Candida albicans; Cell Count; Cell Ontogeny; Cell physiology; Code; Defect; Dendritic Cells; Dermatitis; Development; Dicer Enzyme; Disease; Embryo; Embryonic Development; Fetal Liver; Gene Expression; Gene Expression Profile; Genes; Genetic Translation; Goals; Growth; Homeostasis; ITGAX gene; Imiquimod; Immune; Immune Tolerance; Individual; Infection; Inflammation; Inflammatory; Interruption; Intervention; Knock-in Mouse; Laboratories; Langerhans cell; Life Cycle Stages; Link; Macrophage Colony-Stimulating Factor Receptor; Maintenance; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Monitor; Mus; Mutant Strains Mice; Mutation; Myelogenous; Outcome; Pathway interactions; Procedures; Production; Proteins; Psoriasis; Regulation; Reporting; Research; Ribonuclease III; Role; Signal Pathway; Skin; Small RNA; T cell differentiation; T-Cell Proliferation; Technology; Testing; Translations; Untranslated RNA; Validation; Yolk Sac; adaptive immunity; antigen-specific T cells; base; blastomere structure; cytokine; experience; insight; langerin; macrophage; migration; monocyte; mouse model; mutant; novel; self-renewal; single-cell RNA sequencing; skin disorder; transcriptome sequencing

Abstract Langerhans cells (LCs), the skin residing dendritic cells (DCs), control both the induction of adaptive immunity, and immune tolerance in skin and are involved in variety of skin disease development. However, the regulatory mechanisms involved in the development and functions of LCs have not been completely elucidated. MicroRNAs (miRNAs), a class of non-coding small RNAs, are recognized as important regulators of protein-coding genes through the inhibition of mRNA translation. Using Cre-loxP Dicer deletion mouse models, our laboratory and others have reported that deletion of miRNAs by CD11c-Cre or hLangerin-Cre significantly reduced the number and interrupted the function of LCs, indicating that miRNAs are required for LC homeostasis and function after birth. While there are more than 1000 experimentally reported miRNAs, very few individual miRNAs are linked to LCs so far. We were the first to report that miR-150 and miR-223 differentially regulated LC-induced T cell proliferation and cytokine production. Most recently, our embryonic lineage-tracing studies showed that miRNAs, including miR-17-92 cluster, regulate LC embryonic development. Furthermore, using miRNA arrays, we identified that mature LCs have a unique miRNA gene expression profile compared to immature LCs, and that miRNA expression is dynamically changed during LC embryonic ontogeny. These findings led to our central hypothesis that the dynamically changed miRNAs may serve as critical regulators controlling LC ontogeny, homeostasis and function through fine-tuning specific target genes. In Aim 1, we will investigate the roles of miRNAs in LC ontogeny and homeostasis. Constitutive or inducible Csf1r-specific individual miRNA mutant mice will be used for studying embryonic LC ontogeny and LC repopulation after inflammation, while LC-specific Dicer or individual miRNA mutant mice will be used for LC homeostasis after birth. In Aim 2, we will investigate the roles of miRNAs in LC function, inducible LC-specific Dicer or individual miRNA mutation mouse models will be used. In Aim 3, the direct target gene(s) of miRNAs and related signaling pathways involved in LC development and function will be investigated by the combination of RNA-seq, miRNA bioinformatics and related target functional validation strategies. The proposed studies will uncover the dynamic miRNA-mRNA regulation and related molecular mechanisms and signaling pathways that control LC development and function, which will not only provide new insight into the biology of LCs, but may also facilitate the development of LC-based intervention strategies for diseases.

摘要 朗格汉斯细胞（LC），皮肤驻留树突状细胞（DC），控制两种诱导的免疫反应。 获得性免疫和皮肤免疫耐受，参与多种皮肤疾病的发生 发展然而，在发展和职能的监管机制参与 LCs尚未完全阐明。MicroRNAs（miRNAs）是一类非编码的小分子RNA， RNA被认为是蛋白质编码基因的重要调节因子，通过抑制 mRNA翻译。使用Cre-loxP Dicer缺失小鼠模型，我们的实验室和其他实验室已经 报道，通过CD 11 c-Cre或hLangerin-Cre删除miRNAs显著降低了 数量和中断LC的功能，表明LC需要miRNA 出生后的体内平衡和功能。虽然有超过1000个实验报告 到目前为止，很少有个别的miRNA与LC相关联。我们是第一个报道 miR-150和miR-223差异调节LC诱导的T细胞增殖和细胞因子 生产最近，我们的胚胎谱系追踪研究表明， miR-17-92簇，调控LC胚胎发育。此外，使用miRNA阵列，我们 发现成熟LC与未成熟LC相比具有独特的miRNA基因表达谱， 在LC胚胎个体发育过程中，miRNA的表达是动态变化的。这些 这些发现导致了我们的中心假设，即动态变化的miRNAs可能作为 通过微调特异性调节因子来控制LC个体发育、稳态和功能的关键调节因子， 靶基因在目的1中，我们将研究miRNA在LC个体发育和稳态中的作用。 组成型或诱导型Csf 1 r特异性个体miRNA突变小鼠将用于研究 胚胎LC个体发育和炎症后LC再增殖，而LC特异性Dicer或 单个miRNA突变小鼠将用于出生后的LC体内平衡。在目标2中，我们将 研究miRNA在LC功能、诱导型LC特异性Dicer或单个miRNA中的作用 将使用突变小鼠模型。在目的3中，miRNA的直接靶基因和相关的靶基因被发现。 参与LC发育和功能的信号通路将由 RNA-seq、miRNA生物信息学和相关靶标功能验证的组合 战略布局这些研究将揭示miRNA-mRNA的动态调控及其相关机制。 控制LC发育和功能的分子机制和信号通路， 不仅将为LC的生物学提供新的见解，而且还可能促进 基于LC的疾病干预策略。