MicroRNA regulation of CTGF in hepatic stellate cells

MicroRNA对肝星状细胞CTGF的调控

• 批准号: 9015720
• 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 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9015720
• 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; FDA approved; Fibrillar Collagen; Fibrosis; 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; Untranslated RNA; alcohol exposure; alcohol response; base; cell type; clay; connective tissue growth factor; effective therapy; exosome; fibrogenesis; improved; in vivo; in vivo Model; liver function; liver injury; 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.

描述(申请人提供)：在慢性肝损伤期间，肝星状细胞(HSC)产生和沉积大量的纤维性胶原蛋白，导致疤痕形成和肝功能损害。这种纤维化过程是由结缔组织生长因子(CTGF)推动的。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。本应用的总体目标是确定microRNA-199a(miR-199a)或mircoRNA-214(miR-214)在调节CTGF产生方面的功能，因为我们发现miR-199a/214是迄今未被识别的HSC中作为CTGF mRNA表达负调控因子的miR。因此，miR-199a/214在正常肝脏静止的HSC中高水平表达，从而抑制CTGF的产生，而在HSC损伤后的激活过程中，miR-199a/214的表达被抑制，导致CTGF表达增强。MiR-199a/214是通过纳米尺寸的外切体从HSC输出的，这一新发现很重要，因为它允许miR传递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。[2]建立miR-199a/214在HSC激活和纤维化中的作用[3]建立外体miR-199a/214在细胞间信号转导中的作用这些研究的预期结果将是更全面地了解CTGF在HSC激活过程中的调节方式。这项研究的理论基础是，一旦更好地了解miR-199a/214在CTGF调控中的作用，它们可能会被开发为新型的抗纤维化药物。开发新的治疗方法至关重要，因为纤维化病理是最大的一组疾病，目前还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：肝硬变 西方第九大死因，影响全球数百万人，是一种 是肝癌的先兆。拟议的研究是对2004年跨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，从而对改善公众健康产生积极影响。CTGF生物学对肝纤维化过程和新治疗策略的开发至关重要。