MicroRNA in Liver Development

MicroRNA 在肝脏发育中的作用

• 批准号: 7509250
• 负责人: Joshua R. Friedman
• 金额: $ 8.23万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7509250
• 关键词: Address; Adult; Alleles; Apical; Biliary; Biliary Atresia; Bioinformatics; Biological; Biological Assay; Biological Models; Biological Process; Candidate Disease Gene; Cells; Childhood; Class; Computer Simulation; Congenital Disorders; Cultured Cells; Data; Defect; Development; Disease; Ductal; Embryo; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Models; Goals; Health; Hepatic; Hepatobiliary; Homeostasis; Human; In Vitro; Laboratories; Light; Liver; Liver diseases; Luc Gene; Maintenance; Measures; Methods; MicroRNAs; Microarray Analysis; Microscopic; Modeling; Molecular; Molecular Target; Morphogenesis; Mus; Pathway Analysis; Pathway interactions; Physiological; Plasmids; Process; RNA; RNA Interference; Regulatory Pathway; Reporter; Research; Site; Small RNA; Sodium; Structure; Surveys; System; Tamoxifen; Testing; Transcript; Transfection; Transgenic Mice; United States National Institutes of Health; Zebrafish; base; bile duct; bile salts; design; in vivo; insight; liver transplantation; malformation; mouse model; mutant; promoter; tool

DESCRIPTION (provided by applicant): Project Summary The control of gene expression is at the core of biological development and homeostasis, and developmental pathways are often disrupted in disease processes. This is particularly true in hepatobiliary disease, as illustrated by the existence of over 20 congenital disorders associated with defects in the differentiation, morphogenesis, and maintenance of the bile ducts. This class includes biliary atresia, of which approximately 1/3rd of cases are associated with a developmental defect of the bile ducts (1, 2). In light of the fact that biliary atresia is the most common indication for pediatric liver transplantation, an understanding of the molecular basis of bile duct development may have a significant impact on human health. In recent years, an unexpected form of gene regulation has been discovered in which small RNA molecules known as microRNAs (miRNA) repress the expression of target genes through RNA interference (reviewed in (3-5)). There are over 500 human miRNAs and these may collectively regulate 20-30% of all genes (6-8). Virtually nothing is known regarding the function of miRNA in liver development and disease. To address this, we have performed the first large-scale study of miRNA expression during mouse liver development (see Preliminary Data), resulting in the identification of hepatic miRNAs whose spatio-temporal expression is suggestive of developmental functions. One of these (miR- 30a) is predominantly expressed in the ductal plate and bile ducts. We have utilized the zebrafish model system as a rapid, preliminary assay to test the function of miR-30a. As shown in the Preliminary Studies, zebrafish miR-30a is critical for the normal development and function of bile ducts. This proposal aims to investigate the biological and molecular function of miR-30a in the mammalian liver. In Aim 1, we will derive a mouse model of hepatic miR-30a deficiency and we will measure the effects of this deficiency on biliary structure and function. In Aim 2, we will use this model, a cell culture model, and computational prediction to perform a large-scale survey of miR-30a targets in the liver. The research proposed is significant because it may provide the first demonstration of a requirement for miRNA in liver development and it will significantly add to our limited understanding of the regulatory pathways controlling this biological process. It directly addresses goals of the NIH Action Plan for Liver Research regarding liver development (12). Project Narrative This proposal will study a recently-discovered form of gene regulation during the formation of the the [sic] bile ducts within the liver. This will help us to understand the normal development of the liver and the ways in which that process goes awry in a spectrum of diseases associated with malformations of the bile ducts. Those insights can then be applied towards better treatment of diseases of the liver and bile ducts.

描述（由申请人提供）： 基因表达的控制是生物发育和体内平衡的核心，发育途径在疾病过程中经常被破坏。这在肝胆疾病中尤其如此，如存在超过20种与胆管的分化、形态发生和维持缺陷相关的先天性疾病所示。这类包括胆道闭锁，其中约1/3的病例与胆管发育缺陷有关（1，2）。鉴于胆道闭锁是小儿肝移植最常见的适应症，了解胆管发育的分子基础可能对人类健康产生重大影响。近年来，人们发现了一种意想不到的基因调节形式，其中称为微小RNA（miRNA）的小RNA分子通过RNA干扰抑制靶基因的表达（综述见（3-5））。有超过500种人类miRNA，它们可以共同调节所有基因的20-30%（6-8）。关于miRNA在肝脏发育和疾病中的功能几乎一无所知。为了解决这个问题，我们进行了第一次大规模的研究，在小鼠肝脏发育过程中的miRNA表达（见初步数据），导致识别的肝脏miRNA的时空表达是发育功能的提示。其中之一（miR-30 a）主要在胆管板和胆管中表达。我们已经利用斑马鱼模型系统作为快速的初步测定来测试miR-30 a的功能。如初步研究所示，斑马鱼miR-30 a对胆管的正常发育和功能至关重要。本研究旨在探讨miR-30 a在哺乳动物肝脏中的生物学和分子功能。在目标1中，我们将获得肝脏miR-30 a缺乏的小鼠模型，并测量这种缺乏对胆道结构和功能的影响。在目标2中，我们将使用这个模型，细胞培养模型和计算预测来进行肝脏中miR-30 a靶点的大规模调查。这项研究意义重大，因为它可能首次证明了肝脏发育对miRNA的需求，并将大大增加我们对控制这一生物过程的调控途径的有限理解。它直接解决了NIH肝脏研究行动计划关于肝脏发育的目标（12）。 该项目将研究最近发现的肝脏内胆管形成过程中的基因调控形式。这将有助于我们了解肝脏的正常发育以及该过程在与胆管畸形相关的疾病谱中出错的方式。这些见解可以应用于更好地治疗肝脏和胆管疾病。