MicroRNA in Liver Development

MicroRNA 在肝脏发育中的作用

• 批准号: 7648017
• 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 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7648017
• 关键词: Address; Adult; Alleles; Apical; Biliary; Biliary Atresia; Bioinformatics; Biological; Biological Assay; Biological Models; Biological Process; Candidate Disease Gene; Cell Culture Techniques; Cells; Childhood; 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）： 项目摘要基因表达的控制是生物发育和体内平衡的核心，并且发育途径在疾病过程中经常受到破坏。在肝胆疾病中尤其如此，这是由20多种与胆管分化，形态发生和维持中的缺陷相关的超过20多种先天性疾病所说明的。该类别包括胆道闭锁，其中约1/3病例与胆管的发育缺陷有关（1，2）。鉴于胆道闭锁是小儿肝移植的最常见指征，对胆管发育的分子基础的理解可能会对人类健康产生重大影响。近年来，已经发现了一种意外的基因调节形式，其中称为microRNA（miRNA）的小RNA分子通过RNA干扰抑制靶基因的表达（在（3-5）中进行了综述）。有500多个人类miRNA，这些miRNA可能统称所有基因的20-30％（6-8）。关于miRNA在肝发育和疾病中的功能，几乎一无所知。为了解决这个问题，我们在小鼠肝发育过程中进行了首次对miRNA表达的大规模研究（请参阅初步数据），从而鉴定出肝miRNA的时空表达暗示了发育功能。其中一种（mir-30a）主要在导管板和胆管中表达。我们利用斑马鱼模型系统作为快速的初步测定，以测试miR-30a的功能。如初步研究所示，斑马鱼miR-30a对于胆管的正常发育和功能至关重要。该建议旨在研究miR-30a在哺乳动物肝脏中的生物学和分子功能。在AIM 1中，我们将得出肝脏miR-30a缺陷的小鼠模型，并将测量这种缺陷对胆道结构和功能的影响。在AIM 2中，我们将使用此模型，一个细胞培养模型和计算预测来对肝脏中的miR-30a靶标进行大规模调查。提出的研究很重要，因为它可能会首先证明miRNA在肝发育中的需求，这将大大增加我们对控制这种生物学过程的调节途径的有限理解。它直接解决了有关肝脏发育的NIH行动计划的目标（12）。 项目叙述该提案将研究肝内[SIC]胆管形成期间最近发现的基因调节形式。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一系列疾病中的出现方式。然后可以将这些见解用于更好地治疗肝脏和胆管疾病。

项目成果

Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease.

• DOI: 10.1016/j.metabol.2016.02.014
• 发表时间: 2016-08
• 期刊: Metabolism: clinical and experimental
• 作者: Mota M;Banini BA;Cazanave SC;Sanyal AJ
• 通讯作者: Sanyal AJ

The multifaceted role of natriuretic peptides in metabolic syndrome.

• DOI: 10.1016/j.biopha.2017.05.136
• 发表时间: 2017-08
• 期刊: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
• 作者: Santhekadur PK;Kumar DP;Seneshaw M;Mirshahi F;Sanyal AJ
• 通讯作者: Sanyal AJ

Therapies in non-alcoholic steatohepatitis (NASH).

• DOI: 10.1111/liv.13302
• 发表时间: 2017-01
• 期刊: Liver international : official journal of the International Association for the Study of the Liver
• 作者: Oseini AM;Sanyal AJ
• 通讯作者: Sanyal AJ

Dysregulated Hepatic Methionine Metabolism Drives Homocysteine Elevation in Diet-Induced Nonalcoholic Fatty Liver Disease.

• DOI: 10.1371/journal.pone.0136822
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Pacana T;Cazanave S;Verdianelli A;Patel V;Min HK;Mirshahi F;Quinlivan E;Sanyal AJ
• 通讯作者: Sanyal AJ

Readiness for behaviour change in non-alcoholic fatty liver disease: implications for multidisciplinary care models.

• DOI: 10.1111/liv.12483
• 发表时间: 2015-03
• 期刊: Liver international : official journal of the International Association for the Study of the Liver
• 作者: Stewart KE;Haller DL;Sargeant C;Levenson JL;Puri P;Sanyal AJ
• 通讯作者: Sanyal AJ