MicroRNAs regulate skin Langerhans cells

MicroRNA 调节皮肤朗格汉斯细胞

基本信息

批准号：
10006075
负责人：
Li Zhou
金额：
$ 33.11万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
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/10006075
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 Estrogen receptor positive 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 miRNA expression profiling migration monocyte mouse model mutant novel self-renewal single-cell RNA sequencing skin disorder transcriptome sequencing

项目摘要

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.

抽象的 Langerhans细胞（LCS），属于树突状细胞（DC）的皮肤，都控制着诱导的诱导皮肤的自适应免疫力和免疫耐受性，并参与多种皮肤病发展。但是，涉及开发和功能的监管机制 LC的尚未完全阐明。 microRNA（miRNA），一类非编码小 RNA被认为是蛋白质编码基因的重要调节剂 mRNA翻译。使用Cre-loxp dicer删除鼠标模型，我们的实验室和其他实验室具有报道CD11C-CRE或Hlangerin-Cre删除miRNA可显着降低数量并中断LC的功能，表明LC需要miRNA 稳态和出生后的功能。虽然有1000多个实验报告到目前为止，miRNA，很少有单个miRNA与LCS相关。我们是第一个报告 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，miRNA，包括 miR-17-92簇，调节LC胚胎发育。此外，使用miRNA阵列，我们确定成熟的LC与未成熟相比具有独特的miRNA基因表达谱 LCS，在LC胚胎个体个体发育过程中，miRNA表达会动态改变。这些调查结果导致我们的中心假设，即动态变化的miRNA可能是控制LC个体发育，体内平衡和功能的关键调节器通过微调特定靶基因。在AIM 1中，我们将研究miRNA在LC个体发育和体内平衡中的作用。组成型或诱导的CSF1R特异性单个miRNA突变小鼠将用于研究炎症后的胚胎LC个体发育和LC重生，而LC特异性dicer或出生后，单个miRNA突变小鼠将用于LC稳态。在AIM 2中，我们将研究miRNA在LC功能，诱导LC特异性dicer或单个miRNA中的作用将使用突变鼠标模型。在AIM 3中，miRNA和相关的直接靶基因 LC开发和功能涉及的信号通路将由 RNA-seq，miRNA生物信息学和相关目标功能验证的组合策略。拟议的研究将发现动态miRNA-mRNA调节和相关控制LC发育和功能的分子机制和信号通路，不仅会对LCS的生物学提供新的见解，还可以促进发展基于LC的疾病干预策略。