MicroRNA in Liver Development and Disease

MicroRNA 在肝脏发育和疾病中的作用

• 批准号: 7914267
• 负责人: Joshua R. Friedman
• 金额: $ 31.15万
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914267
• 关键词: Ablation; Address; Anatomy; Antisense Oligonucleotides; Biliary; Biliary Atresia; Biochemical; Bioinformatics; Biological; Biological Assay; Cell Culture Techniques; Cell model; Characteristics; Childhood; Clinical Research; Complement; Cultured Cells; Databases; Development; Disease; Disease Progression; Ductal; Embryo; Embryonic Structures; Excretory function; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Models; Genetic screening method; Goals; Hepatic; Hepatobiliary; Hepatocyte; Homeostasis; Human; Human Genome; In Situ Hybridization; In Vitro; Light; Liver; Liver diseases; Mediating; MicroRNAs; Microanatomy; Modeling; Molecular; Molecular Profiling; Molecular Target; Morphogenesis; Mus; Pathogenesis; Pathway interactions; Play; Proliferating; RNA Interference; Regulatory Pathway; Reporter; Research; Role; Small RNA; Specimen; Surveys; System; Testing; Tissues; United States National Institutes of Health; Work; bile duct; biliary tract; cholangiocyte; human DICER1 protein; in vivo; insight; intrahepatic; liver transplantation; mouse model; novel; tool

DESCRIPTION (provided by applicant): The control of gene expression is at the core of biological development and homeostasis. In recent years, an unexpected form of gene regulation has been discovered in which small RNA molecules known as microRNAs (miRNAs) repress the expression of target genes through RNA interference. There are over 500 miRNAs in the human genome, and collectively they may regulate 20-30% of all genes. Virtually nothing is known regarding the function of miRNA in liver development and disease. To address this, we have quantified the expression of all miRNAs during mouse liver development. We have identified a set of miRNAs whose expression rises significantly during the period of hepatobiliary differentiation and morphogenesis, and we have begun to localize their expression by in situ hybridization. This approach has yielded the first examples of developmentally regulated miRNAs in the embryonic liver. One miRNA (miR-30a) is expressed in the ductal plate and bile ducts. Our preliminary work on miR-30a has resulted in the first evidence of a requirement for a miRNA in biliary development. The function of miR-30a and other hepatic miRNAs will be assessed in a cell culture model of liver differentiation (Aim 1A). This system will be also be used to identify the molecular targets of hepatic miRNAs (Aim 1A). The mouse genetic model will be used to test the developmental function of miR-30a and selected miRNAs in vivo (Aim 1B). Many diseases are caused by aberrations in normal developmental pathways. Biliary atresia, the leading indication for pediatric liver transplantation, is associated with developmental anomalies. Despite considerable efforts, its cause is unknown. The role of miRNA in biliary atresia has never been explored, although we have found that miR-30a is highly expressed in the proliferating bile ducts characteristic of biliary atresia. We will utilize specimens collected as part of the Biliary Atresia Resarch Consortium clinical study to characterize the expression of all miRNA in biliary atresia tissue and controls (Aim 2A). This will be complemented by a parallel study using a mouse model of biliary atresia. The pathogenic role of miRNA will then be tested by inhibition of miRNAs in the mouse model (Aim 2B). These studies have the potential to shed light on biliary atresia pathogenesis and may result in new treatments. The research proposed is significant because it will reveal novel regulatory pathways in normal liver development and in biliary atresia. It directly addresses goals of the NIH Action Plan for Liver Research regarding liver development and identification of the cause of biliary atresia.

描述（由申请人提供）： 基因表达的控制是生物发育和稳态的核心。在 近年来，已经发现了一种意外的基因调节形式，其中小RNA 分子称为microRNA（miRNA）通过RNA抑制靶基因的表达 干涉。人类基因组中有500多个miRNA，共同 调节所有基因的20-30％。关于miRNA在肝脏中的功能几乎一无所知 发展与疾病。 为了解决这个问题，我们已经量化了小鼠肝发育过程中所有miRNA的表达。我们已经确定了一组miRNA，它们在肝胆管分化和形态发生期间的表达显着升高，并且我们开始通过原位杂交来定位它们的表达。这种方法得出了胚胎肝中发育调节的miRNA的第一个例子。一个miRNA（miR-30a）在导管板和胆管中表达。我们在miR-30a上的初步工作导致了第一个证据表明需要miRNA在胆道发展中。 miR-30a和其他肝miRNA的功能将在肝分化的细胞培养模型中进行评估（AIM 1A）。该系统还将用于识别肝miRNA的分子靶标（AIM 1A）。小鼠遗传模型将用于测试miR-30a和选定的MiRNA在体内的发育功能（AIM 1B）。 许多疾病是由正常发育途径中的畸变引起的。胆道闭锁是小儿肝移植的主要指示，与发育异常有关。尽管做出了巨大的努力，但其原因还是未知的。 miRNA在胆道闭锁中的作用从未被探索过，尽管我们发现miR-30a在胆道闭锁的增殖胆管特征中高度表达。我们将利用收集的标本作为胆道闭锁临床临床研究的一部分，以表征所有miRNA在胆道闭锁组织和对照中的表达（AIM 2A）。使用胆道闭锁的小鼠模型的平行研究将补充这一点。然后，将通过在小鼠模型中抑制miRNA（AIM 2B）来测试miRNA的致病作用。这些研究有可能阐明胆道闭锁的发病机理，并可能导致新的治疗方法。 提出的研究很重要，因为它将揭示正常肝发育和胆道闭锁的新调节途径。它直接解决了有关肝脏开发和鉴定胆道闭锁原因的NIH行动计划的目标。