MicroRNA regulation of CTGF in hepatic stellate cells

MicroRNA对肝星状细胞CTGF的调控

• 批准号: 8275273
• 负责人: DAVID R BRIGSTOCK
• 金额: $ 32.58万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-05 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8275273
• 关键词: 3' Untranslated Regions; Accounting; Affect; Alcohols; Autoimmune Process; Automobile Driving; Binding; Biogenesis; Biology; Cause of Death; Cell Cycle Progression; Cell Proliferation; Cells; Cellular biology; Cessation of life; Chronic; Cicatrix; Collagen; Deposition; Development; Disease; E-Box Elements; Elements; Epithelial; Ethanol; Exposure to; FDA approved; Fibrillar Collagen; Fibrosis; Functional RNA; Gene Targeting; Genes; Genetic; Genetic Transcription; Goals; Health; Heart; Hepatic Stellate Cell; Hepatocyte; Human; Immigration; Individual; Injury; Introns; Kidney; Knowledge; Lead; Light; Liposomes; Liver; Liver Cirrhosis; Liver Fibrosis; Liver diseases; Lung; Malignant neoplasm of liver; Medical; Mesenchymal; Metabolism; MicroRNAs; Mus; Organ; Outcome Study; Pancreas; Pathology; Pathway interactions; Pattern; Play; Post-Transcriptional Regulation; Process; Production; Public Health; RNA; Regulation; Research; Role; Signal Transduction; Skin; Smooth Muscle Actin Staining Method; Testing; Therapeutic; Therapeutic Intervention; Tissues; Toxin; Transcript; Transforming Growth Factors; United States National Institutes of Health; alcohol response; base; cell type; clay; connective tissue growth factor; effective therapy; fibrogenesis; improved; in vivo; in vivo Model; liver function; mRNA Expression; nanoscale; nanosized; novel; novel therapeutics; promoter; response; stemness

DESCRIPTION (provided by applicant): During chronic liver injury, hepatic stellate cells (HSC) produce and deposit excessive quantities of fibrillar collagens leading to scar formation and compromised liver function. This fibrotic process is driven by connective tissue growth factor (CTGF). Our broad long-term objective is to inhibit the production or action or CTGF so that effective anti-fibrotic strategies can be developed for use in humans. The overall objective of this application is to determine the function of microRNA-199a (miR-199a) or mircoRNA-214 (miR-214) in regulating CTGF production in light of our identification of miR-199a/214 as hitherto unrecognized miRs in HSC which function as negative regulators of CTGF mRNA expression. Thus miR-199a/214 are expressed at high levels in quiescent HSC in normal liver thereby inhibiting CTGF production whereas their expression is suppressed during HSC activation after injury leading to enhanced CTGF expression. MiR-199a/214 are exported from HSC via nano-size exosomes, a novel finding that is important since it allows for miR delivery to neighboring cells and regulation of target genes therein. Our central hypothesis is that expression or action of miR-199a/214 in HSC are critical determinants of CTGF mRNA expression. The Aims to test our hypothesis are: [1] Establish mechanisms regulating miR-199a/214 production in HSC [2] Establish the role of miR-199a/214 in HSC activation and fibrosis [3] Establish the role of exosomal miR-199a/214 in intercellular signaling The expected outcome of these studies will be a more complete understanding of the manner in which CTGF production is regulated during HSC activation. The rationale that underlies the proposed research is that once the roles of miR-199a/214 in CTGF regulation are better understood, they may be exploitable as novel anti- fibrotics. Development of new therapies is critical because fibrotic pathology represents one of the largest groups of disorders for which there is no effective therapy. The medical and financial burdens of liver fibrosis are huge: liver cirrhosis is the ninth leading cause of death in the West, affects millions of individuals world- wide, and is a harbinger of hepatic cancer. The proposed studies are responsive to the 2004 trans-NIH "Action Plan for Liver Disease Research and will have a positive impact on improving public health by providing new leads in our understanding of CTGF biology, which is central to the process of liver fibrosis and the development of novel therapeutic strategies. PUBLIC HEALTH RELEVANCE: Fibrosis of internal organs is a significant contributing factor in about 45% of the deaths in the USA yet there are currently no FDA-approved anti-fibrotic therapeutics. Chronic fibrosis most commonly affects the liver, lung, kidney, heart, pancreas and skin and is the result of diverse causes such as autoimmune, genetic, idiopathic, or toxins (e.g. alcohol in hepatic fibrosis). These studies will determine the role of connective tissue growth factor (CTGF) in controlling the pro-fibrogenic functions of hepatic stellate cells, which are the principal fibrogenic cell type in the liver. This proposal focuses on identifying the mechanisms by which CTGF production is regulated by small naturally occurring RNA molecules called microRNA. The relevance of these studies is that they will identify key steps in the pathways that lead to hepatic fibrosis and will define points of therapeutic intervention that exploit the central role played by connective tissue growth factor (CTGF) in driving fibrotic pathology.

描述（由申请方提供）：在慢性肝损伤期间，肝星状细胞（HSC）产生并存款过量的纤维状胶原，导致瘢痕形成和肝功能受损。这种纤维化过程是由结缔组织生长因子（CTGF）驱动的。我们广泛的长期目标是抑制CTGF的产生或作用，以便开发有效的抗纤维化策略用于人类。本申请的总体目的是根据我们鉴定的miR-199a/214作为迄今为止未被认识的HSC中的miR（其作为CTGF mRNA表达的负调节剂起作用）来确定microRNA-199a（miR-199a）或microRNA-214（miR-214）在调节CTGF产生中的功能。因此，miR-199a/214在正常肝脏中的静止HSC中以高水平表达，从而抑制CTGF产生，而它们的表达在损伤后的HSC活化期间受到抑制，导致CTGF表达增强。miR-199a/214通过纳米大小的外泌体从HSC输出，这是一个重要的新发现，因为它允许miR递送到邻近细胞并调节其中的靶基因。我们的中心假设是miR-199a/214在HSC中的表达或作用是CTGF mRNA表达的关键决定因素。检验我们假设的目的是：[1]建立调控HSC中miR-199a/214产生的机制[2]建立miR-199a/214在HSC活化和纤维化中的作用[3]建立外泌体miR-199a/214在HSC活化和纤维化中的作用[4]建立外泌体miR-199a/214在HSC活化和纤维化中的作用[5]建立外泌体miR-199a/214在HSC活化和纤维化中的作用[6]建立外泌体miR-199a/214在HSC活化和纤维化中的作用[7]建立外泌体miR-199a/214在HSC活化和纤维化中的作用[8]建立外泌体miR-199a/214在HSC活化和纤维化中的作用[8]建立外泌体miR-199a/214在HSC活化和纤维化中的作用[8]建立外泌体miR-199a/214在HSC活化和纤维化中的这些研究的预期结果将是更完整地了解CTGF产生在细胞间信号传导中的调节方式。HSC激活。所提出的研究的基本原理是，一旦更好地理解了miR-199a/214在CTGF调节中的作用，它们就可能被开发为新型抗纤维化药物。开发新的治疗方法是至关重要的，因为纤维化病理学代表了最大的疾病组之一，对此没有有效的治疗方法。肝纤维化的医疗和经济负担是巨大的：肝硬化是 是西方国家的第九大死因，影响着全世界数百万人， 肝癌的先兆。拟议的研究是对2004年trans-NIH "肝病研究行动计划"的响应，并将通过为我们对CTGF生物学的理解提供新的线索，对改善公共卫生产生积极影响，CTGF生物学是肝纤维化过程和新治疗策略开发的核心。 公共卫生关系：内脏纤维化是美国约45%死亡的重要因素，但目前还没有FDA批准的抗纤维化疗法。慢性纤维化最常影响肝、肺、肾、心脏、胰腺和皮肤，并且是多种原因如自身免疫、遗传、特发性或毒素（例如肝纤维化中的酒精）的结果。这些研究将确定结缔组织生长因子（CTGF）在控制肝星状细胞促纤维化功能中的作用，肝星状细胞是肝脏中主要的纤维化细胞类型。这项建议的重点是通过以下方式确定机制： CTGF的产生是由称为microRNA的天然存在的小RNA分子调节的。这些研究的相关性在于，它们将确定导致肝纤维化的途径中的关键步骤，并将确定利用结缔组织生长因子（CTGF）在驱动纤维化病理中发挥的核心作用的治疗干预点。