miRNAs and epidermal langerhans cell development and function

miRNA 和表皮朗格汉斯细胞的发育和功能

• 批准号: 8131739
• 负责人: QING-SHENG MI
• 金额: $ 16.07万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-19 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8131739
• 关键词: Affect; Antigen Presentation; Antigen-Presenting Cells; Autoimmune Diseases; Bone Marrow; C-Type Lectins; Cell Maturation; Cell Therapy; Cells; Code; Communicable Diseases; Dendritic Cells; Development; Dicer Enzyme; Epidermis; Equilibrium; Exhibits; Functional RNA; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic Translation; Goals; Hematopoietic stem cells; Homeostasis; Immune; Immunity; Infection; Intervention; Knock-in Mouse; Knock-out; Knowledge; Laboratories; Langerhans cell; Life Cycle Stages; Malignant Neoplasms; Messenger RNA; MicroRNAs; Molecular; Molecular Profiling; Mouse Strains; Mus; Mutant Strains Mice; Pathway interactions; Pattern; Play; Population Heterogeneity; Process; Proteins; RNA; Regulator Genes; Reporting; Reverse Transcriptase Polymerase Chain Reaction; Ribonuclease III; Role; Skin; Small RNA; Sorting - Cell Movement; Stem cells; T-Lymphocyte; Testing; Thymus Gland; Time; Tissues; Translations; Validation; base; enhanced green fluorescent protein; human DICER1 protein; langerin; lymph nodes; macrophage; migration; mouse model; novel; promoter; protein expression; public health relevance

DESCRIPTION (provided by applicant): Dendritic cells (DCs), a heterogeneous population originating from hematopoietic stem cells (HSCs) in the bone marrow (BM), are professional antigen-presenting cells that play key roles in determining the balance between immunity and tolerance induction. Langerhans cells (LCs) are skin-resident DCs that express the C-type lectin Langerin and have a life cycle distinct from many other types of DCs. Even though LCs were first described more than 100 years ago, their development and immunological functions still remain enigmatic. MicroRNAs (miRNAs), a class of 21-25 nt single-stranded non-coding small RNAs, are increasingly being recognized as important regulators of gene expression through the inhibition of effective mRNA translation. The ribonuclease III enzyme Dicer is required for the processing of mature and functional miRNAs. Using Cre-loxP tissue-specific Dicer deletion, our laboratory and others have reported that deletion of miRNAs in HSCs significantly affects the development and function of different immune cells. However, the role of miRNAs in the development of LCs is still currently unknown. To test the roles of miRNAs in the development of LCs, we generated a new mouse strain with tissue- specific disruption of Dicer in LCs using Langerin-Cre. Surprisingly, mice with miRNAs-deficiency in LCs had significantly reduced number of epidermal LCs and the expression of Langerin was significantly reduced in miRNA-deficient LCs. Furthermore, LCs have a specific miRNA gene expression profile compared to other immune cells. Thus, our central hypothesis is that miRNAs are very important components of the molecular circuitry that controls LC development and function. We will test our hypothesis by pursuing the following three Specific Aims: 1) To determine the expression patterns of miRNAs during LC maturation; 2) To investigate the role of miRNAs in LC development and function; 3) To identify the target genes of miRNAs involved in LC development. Our study will dramatically advance our knowledge on the molecular mechanisms underlying LC development and function, and may also facilitate the development of new intervention strategies for cancer, infectious and autoimmune diseases. PUBLIC HEALTH RELEVANCE: Langerhans cells (LCs) are skin-resident DCs that maintain skin homeostasis, but the detailed molecular pathways regulating LC development and function remain largely unknown. MicroRNAs (miRNAs) are a recently discovered class of evolutionarily conserved small non-coding RNAs that negatively regulate the expression of protein-coding genes. The overall goal of this proposal is to identify the LC-specific miRNA expression profile during development and define their function and direct targets. The results from the above pioneering studies may not only illuminate the new immunological and molecular mechanisms underlying LC development, but may also facilitate the development of new intervention strategies for related autoimmune diseases, infection, and cancer based on the LC cell therapy.

描述（由申请人提供）： 树突状细胞 (DC) 是源自骨髓 (BM) 中造血干细胞 (HSC) 的异质群体，是专业的抗原呈递细胞，在确定免疫和耐受诱导之间的平衡方面发挥着关键作用。朗格汉斯细胞 (LC) 是皮肤驻留 DC，表达 C 型凝集素 Langerin，并且具有与许多其他类型 DC 不同的生命周期。尽管 LC 在 100 多年前就被首次描述，但它们的发育和免疫功能仍然是个谜。 MicroRNA (miRNA) 是一类 21-25 nt 单链非编码小 RNA，通过抑制有效 mRNA 翻译，越来越多地被认为是基因表达的重要调节因子。核糖核酸酶 III 酶 Dicer 是加工成熟和功能性 miRNA 所必需的。使用Cre-loxP组织特异性Dicer删除，我们的实验室和其他人报道HSC中miRNA的删除显着影响不同免疫细胞的发育和功能。然而，miRNA 在 LC 发育中的作用目前仍不清楚。为了测试 miRNA 在 LC 发育中的作用，我们使用 Langerin-Cre 生成了一种新的小鼠品系，该小鼠品系在 LC 中对 Dicer 进行了组织特异性破坏。令人惊讶的是，LC 中 miRNA 缺陷的小鼠表皮 LC 数量显着减少，并且 miRNA 缺陷 LC 中 Langerin 的表达显着减少。此外，与其他免疫细胞相比，LC 具有特定的 miRNA 基因表达谱。因此，我们的中心假设是 miRNA 是控制 LC 发育和功能的分子电路的非常重要的组成部分。我们将通过追求以下三个具体目标来检验我们的假设：1）确定 LC 成熟过程中 miRNA 的表达模式； 2）研究miRNA在LC发育和功能中的作用； 3) 鉴定参与LC发育的miRNA的靶基因。我们的研究将极大地增进我们对 LC 发育和功能分子机制的了解，并且还可能促进针对癌症、传染病和自身免疫性疾病的新干预策略的开发。 公共卫生相关性： 朗格汉斯细胞（LC）是皮肤驻留的 DC，可维持皮肤稳态，但调节 LC 发育和功能的详细分子途径仍然很大程度上未知。 MicroRNA (miRNA) 是最近发现的一类进化上保守的小非编码 RNA，可负调控蛋白质编码基因的表达。该提案的总体目标是确定开发过程中 LC 特异性 miRNA 的表达谱，并定义其功能和直接靶标。上述开创性研究的结果不仅可能阐明LC发展背后的新的免疫学和分子机制，而且可能有助于基于LC细胞疗法开发针对相关自身免疫性疾病、感染和癌症的新干预策略。

项目成果

microRNA miR-17-92 cluster is highly expressed in epidermal Langerhans cells but not required for its development.

microRNA miR-17-92 簇在表皮朗格汉斯细胞中高度表达，但不是其发育所必需的。

• 发表时间: 2014-01
• 影响因子: 5
• 作者: Zhou, L;Qi, R;Liu, M;Xu, Y;Li, G;Weiland, M;Kaplan, D H;Mi, Q
• 通讯作者: Mi, Q

Lack of microRNA miR-150 reduces the capacity of epidermal Langerhans cell cross-presentation.

缺乏 microRNA miR-150 会降低表皮朗格汉斯细胞交叉呈递的能力。

• 发表时间: 2012-11
• 影响因子: 3.6
• 作者: Mi, Qing;Xu, Ying;Qi, Rui;Shi, Yu;Zhou, Li
• 通讯作者: Zhou, Li

Aging affects epidermal Langerhans cell development and function and alters their miRNA gene expression profile.

衰老会影响表皮朗格汉斯细胞的发育和功能，并改变其 miRNA 基因表达谱。

• 发表时间: 2012-11
• 作者: Xu, Ying;Qi, Rui;Chen, Wenbin;Shi, Yuling;Cui, Zhi;Gao, Xing;Chen, Hong;Zhou, Li;Mi, Qing
• 通讯作者: Mi, Qing

miRNA miR-17-92 cluster is differentially regulated in the imiqumod-treated skin but is not required for imiqumod-induced psoriasis-like dermatitis in mice.

miRNA miR-17-92 簇在咪喹莫特治疗的皮肤中受到差异性调节，但对于咪喹莫特诱导的小鼠牛皮癣样皮炎来说不是必需的。

• 发表时间: 2017
• 影响因子: 3.6
• 作者: Wu, Dinghong;Bi, Xinling;Qu, Le;Han, Ling;Yin, Congcong;Deng, Jingwen;Dong, Zheng;Mi, Qing;Zhou, Li
• 通讯作者: Zhou, Li

Systemic analyses of immunophenotypes of peripheral T cells in non-segmental vitiligo: implication of defective natural killer T cells.

非节段性白癜风外周 T 细胞免疫表型的系统分析：自然杀伤 T 细胞缺陷的影响。

• 发表时间: 2012-09
• 影响因子: 4.3
• 作者: Zhou, Li;Li, Kai;Shi, Yu;Hamzavi, Iltefat;Gao, Tian;Henderson, Marsha;Huggins, Richard H;Agbai, Oma;Mahmoud, Bassel;Mi, Xiaofan;Lim, Henry W;Mi, Qing
• 通讯作者: Mi, Qing