miR-200 miRNAs regulate motile ciliogenesis in respiratory epithelia

miR-200 miRNA 调节呼吸道上皮细胞的运动纤毛发生

• 批准号: 9317740
• 负责人: Lin He
• 金额: $ 23.55万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-03 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9317740
• 关键词: Air; Automobile Driving; Biology; Birth; Cell Cycle; Cell physiology; Cells; Cellular biology; Centrioles; Cilia; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Complex; Defect; Defense Mechanisms; Development; Disease; Docking; Electron Microscopy; Embryo; Epidermis; Epithelial; Exhibits; Extracellular Fluid; Family; Functional disorder; Gene Expression Regulation; Genes; Genetic; Genetic Techniques; Genetic Transcription; Goblet Cells; Human; Impairment; Invaded; Knockout Mice; Liquid substance; Lung; Mediating; Messenger RNA; MicroRNAs; Microscopy; Molecular; Molecular Biology; Molecular Genetics; Movement; Mucous body substance; Mucus-Secreting Cell; Mus; Pattern; Phenotype; Play; Process; Proteins; Rana; Regulation; Regulator Genes; Resolution; Respiratory System; Respiratory Tract Infections; Respiratory tract structure; Role; Structure of respiratory epithelium; System; Therapeutic Agents; Tissues; Untranslated RNA; Xenopus; cell motility; ciliopathy; cilium biogenesis; cilium motility; diagnostic biomarker; gene repression; genome editing; insight; kinetosome; mammalian genome; mortality; mouse model; novel; novel diagnostics; particle; pathogen; postnatal; respiratory; screening; therapeutic target

In respiratory epithelia, goblet cells secrete mucus to trap foreign particles and invading pathogens; multiciliated cells (MCCs) provide synchronized beating of motile cilia, driving the extruded mucus out of the respiratory tract. The coordinated functions of MCCs and goblet cells constitute the basis for defense mechanism against respiratory infections. A single MCC contains hundreds of motile cilia that beat coordinately to generate continuous and directional movement of extracellular fluid for pulmonary clearance. Hence the motile ciliogenesis in MCCs is particularly important for the pulmonary defense in respiratory epithelia. Although it has become increasingly clear that non-coding RNAs are integral components of the molecular network for development and disease, most studies on motile ciliogenesis and MCC bioology have focused on protein- coding genes. Using mouse models, our preliminary studies identified miR-200 miRNAs with an essential role in respiratory epithelia. The miR-200 family consists of five highly homologous and evolutionarily conserved miRNAs that collectively exhibit a high-level expression in respiratory epithelia, and particularly, in multiciliated cells. The redundancy of the miR-200 family in the mammalian genome, combined with their strong expression patterns in multiciliated cells, confer a robust functional regulation on motile ciliogenesis. Mice deficient for all miR-200 miRNAs die postnatally, exhibiting strong respiratory dysfunction, excessive mucus accumulation and impaired motile ciliogenesis. Using mouse and frog genetics, cell biology and molecular biology approaches, we proposed to carefully characterize the phenotype in miR-200 deficient MCCs in mouse and in human, with a particular focus on motile ciliagenesis. In addition, we propose to investigate the molecular mechanisms underlying the miR-200 functions during motile ciliogenesis. Taken together, these proposed studies will not only deepen our understanding on the molecular basis of motile ciliogenesis, but also provide important insights into the development of new diagnostic markers and therapeutical agents for treating respiratory conditions.

在呼吸道上皮细胞中，杯状细胞分泌粘液来捕获外来颗粒并入侵 病原体；多纤毛细胞（MCC）提供活动纤毛的同步跳动，驱动 将粘液挤出呼吸道。 MCC 和杯状细胞的协调功能 构成呼吸道感染防御机制的基础。单个 MCC 包含 数百个活动纤毛协调跳动以产生连续和定向运动 细胞外液用于肺部清除。因此，MCC 中的运动纤毛发生特别重要 对于呼吸道上皮的肺防御很重要。虽然已经变得越来越 明确非编码 RNA 是发育分子网络的组成部分 和疾病，大多数关于运动纤毛发生和 MCC 生物学的研究都集中在蛋白质 编码基因。使用小鼠模型，我们的初步研究鉴定了 miR-200 miRNA 在呼吸道上皮细胞中发挥重要作用。 miR-200家族由五个高度同源且 进化上保守的 miRNA 在呼吸系统中共同表现出高水平表达 上皮细胞，特别是多纤毛细胞。 miR-200家族的冗余 哺乳动物基因组，结合其在多纤毛细胞中的强烈表达模式，赋予 对运动纤毛发生的强大功能调节。缺乏所有 miR-200 miRNA 的小鼠死亡 出生后，表现出强烈的呼吸功能障碍、过多的粘液积聚和 运动性纤毛发生受损。利用小鼠和青蛙遗传学、细胞生物学和分子生物学 方法，我们建议仔细表征 miR-200 缺陷型 MCC 的表型 小鼠和人类，特别关注运动纤毛发生。此外，我们建议 研究运动过程中 miR-200 功能的分子机制 纤毛发生。总而言之，这些拟议的研究不仅将加深我们对 运动纤毛发生的分子基础，同时也为纤毛发生的发展提供了重要的见解 用于治疗呼吸系统疾病的新诊断标记物和治疗剂。